Pyrimidine A2B selective antagonist compounds, their synthesis and use

ABSTRACT

The subject invention provides compounds having the structure:  
                 
 
wherein R 1  is substituted or unsubstituted phenyl or a 5-6 membered heterocyclic or heteroaromatic ring containing from 1 to 5 heteroatoms; R 2  is hydrogen, or a substituted or unsubstituted alkyl, —C(O)-alkyl, —C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety; R 3  is hydrogen, or a substituted or unsubstituted alkyl, —C(O)-alkyl, —C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety, or R 2  and R 3  are joined to form a heterocyclic ring; wherein the dashed line represents a second bond which may be present or absent, and when present R 3  is oxygen; R 4  and R 5  are each independently substituted or unsubstituted alkyl, —C(O)-alkyl, —C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety, or R 4 NR 5  together form a substituted or unsubstituted monocyclic or bicyclic, heterocyclic or heteroaryl moiety containing from 1 to 6 heteroatoms; R 12  is hydrogen, alkyl, halogen or cyano; and n is 0, 1, 2, 3 or 4, or an enantiomer, or a specific tautomer, or a pharmaceutically acceptable salt thereof and a method for treating a disease associated with the A 2b  adenosine receptor by administering a therapeutically effective amount of the compounds of the invention.

This application claims the benefit of U.S. Provisional Application No.60/342,595, filed Dec. 20, 2001; the contents of which are herebyincorporated by reference.

Throughout this application, various publications are referenced by fullcitations. The disclosures of these publications in their entireties arehereby incorporated by reference into this application in order to morefully describe the state of the art as known to those skilled therein asof the date of the invention described and claimed herein.

BACKGROUND OF THE INVENTION

Adenosine is an ubiquitous modulator of numerous physiologicalactivities, particularly within the cardiovascular and nervous systems.The effects of adenosine appear to be mediated by specific cell surfacereceptor proteins. Adenosine modulates diverse physiological functionsincluding induction of sedation, vasodilation, suppression of cardiacrate and contractility, inhibition of platelet aggregability,stimulation of gluconeogenesis and inhibition of lipolysis. In additionto its effects on adenylate cyclase, adenosine has been shown to openpotassium channels, reduce flux through calcium channels, and inhibit orstimulate phosphoinositide turnover through receptor-mediated mechanisms(See for example, C. E. Muller and B. Stein “Adenosine ReceptorAntagonists: Structures and Potential Therapeutic Applications,” CurrentPharmaceutical Design, 2:501 (1996) and C. E. Muller “A₁-AdenosineReceptor Antagonists,” Exp. Opin. Ther. Patents 7(5):419 (1997)).

Adenosine receptors belong to the superfamily of purine receptors whichare currently subdivided into P₁ (adenosine) and P₂ (ATP, ADP, and othernucleotides) receptors. Four receptor subtypes for the nucleosideadenosine have been cloned so far from various species including humans.Two receptor subtypes (A₁ and A_(2a)) exhibit affinity for adenosine inthe nanomolar range while two other known subtypes A_(2b) and A₃ arelow-affinity receptors, with affinity for adenosine in thelow-micromolar range. A₁ and A₃ adenosine receptor activation can leadto an inhibition of adenylate cyclase activity, while A_(2a) and A_(2b)activation causes a stimulation of adenylate cyclase.

A few A₁ antagonists have been developed for the treatment of cognitivedisease, renal failure, and cardiac arrhythmias. It has been suggestedthat A_(2a) antagonists may be beneficial for patients suffering fromMorbus Parkinson (Parkinson's disease). Particularly in view of thepotential for local delivery, adenosine receptor antagonists may bevaluable for treatment of allergic inflammation and asthma. Availableinformation (for example, Nyce & Metzger “DNA antisense Therapy forAsthma in an Animal Model” Nature (1997) 385: 721-5) indicates that inthis pathophysiologic context, A₁ antagonists may block contraction ofsmooth muscle underlying respiratory epithelia, while A_(2b) or A₃receptor antagonists may block mast cell degranulation, mitigating therelease of histamine and other inflammatory mediators. A_(2b) receptorshave been discovered throughout the gastrointestinal tract, especiallyin the colon and the intestinal epithelia. It has been suggested thatA_(2b) receptors mediate cAMP response (Strohmeier et al., J. Bio. Chem.(1995) 270:2387-94).

A_(2b) receptors have also been implicated in wide variety ofphysiological activities, thereby suggesting that treatment ofassociated disorders can be effected by blocking the A_(2b) receptor.For example, A_(2b) receptor sites play a role in the degranulation ofmast cells and hence in the treatment of asthma, myocardial reperfusioninjury, allergic reactions including but not limited to rhinitis, poisonivy induced responses, urticaria, scleroderm arthritis, other autoimmunediseases and inflammatory bowel diseases (Gao, Z. et al., J. Biol. Chem.(1999), 274(9):5972-5980, Linden, J. et al., Life Sciences (1998),62(17-18):1519-1524 and U.S. Pat. No. 6,117,878, issued Sep. 12, 2000).A_(2b) receptors have also been shown to inhibit the growth of cardiacfibroblasts, thereby suggesting that they may prevent cardiac remodelingassociated with hypertension, myocardial infarction and myocardialreperfusion after ischemia (Dubey, R. K. et al., Hypertension (2001),37:716-721), mediate the role of adenosine in lymphocyte activation(Mirabet, M. et al., J. Cell. Sci. (1999), 112(4):491-502), regulatevasodilation and growth (Ralevic, V. and Burnstock, G., Pharmacol. Rev.(1998), 50(3):413-492, Corset, V. et al., Nature (2000),407(6805):747-750, and Haynes, J. Jr. et al., Am. J. Physiol. (1999),276(6):H1877-83), participate in neural reflexes in the human gut(Christofi, F. L. et al., J. Comp. Neurol. (2001), 439(1):46-64), andregulate retinal angiogenesis—thereby suggesting the use of A_(2b)antagonists in treating diseases associated with abberantneovascularization such as diabetic retinopathy and retinopathy ofprematurity (Grant, M. B. et al., Invest. Opthalmol. Vis. Sci. (2001),42(9):2068-2073). They are also involved in the modulation of intestinaltone and secretion and neurotransmission and neurosecretion (Feoktistov,I. and Biaggioni, I., Pharmacol. Rev. (1997), 49(4):381-402).

A_(2b) receptors are also coupled to Gs/Gq signaling which has beenshown to be involved in cellular transformations such as cellularinvasion (Faivre, K. et al., Molecular Pharmacology (2001), 60:363-372and Regnauld, K. et al., Oncogene (2002), 21(25):4020-4031), therebysuggesting that treatment of cancer can be effected with A_(2b)antagonists.

Adenosine receptors have also been shown to exist on the retinas ofvarious mammalian species including bovine, porcine, monkey, rat, guineapig, mouse, rabbit and human (See, Blazynski et al., “DiscreteDistributions of Adenosine Receptors in Mammalian Retina,” Journal ofNeurochemistry, volume 54, pages 648-655 (1990); Woods et al.,“Characterization of Adenosine A₁-Receptor Binding Sites in BovineRetinal Membranes,” Experimental Eye Research, volume 53, pages 325-331(1991); and Braas et al., “Endogenous adenosine and adenosine receptorslocalized to ganglion cells of the retina,” Proceedings of the NationalAcademy of Science, volume 84, pages 3906-3910 (1987)). Recently,Williams reported the observation of adenosine transport sites in acultured human retinal cell line (Williams et al., “Nucleoside TransportSites in a Cultured Human Retinal Cell Line Established By SV-40 TAntigen Gene,” Current Eye Research, volume 13, pages 109-118 (1994)).

Compounds which regulate the uptake of adenosine have previously beensuggested as potential therapeutic agents for the treatment of retinaland optic nerve head damage. In U.S. Pat. No. 5,780,450 to Shade, Shadediscusses the use of adenosine uptake inhibitors for treating eyedisorders. Shade does not disclose the use of specific A₃ receptorinhibitors. The entire contents of U.S. Pat. No. 5,780,450 are herebyincorporated herein by reference. Compounds specific to the adenosineA₁, A_(2a) and A₃ receptors and their uses thereof have been previouslydisclosed in PCT International Publication Nos. WO 99/62518 and WO01/39777 A1. The entire contents of PCT International Publication Nos.WO 99/62518 and WO 01/39777 A1 are hereby incorporated herein byreference.

PCT International Publication No. WO 99/64407 generically disclosesα-(1-piperazinyl)acetamido arenecarboxylic acid derivatives asantidaibetic agents. However, the compounds disclosed differ from thecompounds of the present invention in that they have a carboxylic acidgroup rather than an amino group attached to the central ring. Inaddition, the cited application does not exemplify any compounds inwhich the central ring is pyrimidine or any compounds which have aphenyl ring or a heterocyclic ring attached to the central aryl ring.

PCT International Publication No. WO 97/47601 discloses fusedheterocyclic compounds having D₄ and D₂ receptor activity. The disclosedcompounds differ from the compounds of the present invention in that thecentral ring structure is bicyclic in WO 97/47601 rather than monocyclicas in the compounds of the present invention, and the central ringstructure in WO 97/47601 does not allow for an additional aminoalkylsubstituent.

Additional adenosine receptor antagonists are needed as pharmacologicaltools and are of considerable interest as drugs for the above-referenceddisease states and/or conditions.

SUMMARY OF THE INVENTION

The subject invention provides compounds having the structure:

wherein

-   -   R₁ is substituted or unsubstituted phenyl or a 5-6 membered        heterocyclic or heteroaromatic ring containing from 1 to 5        heteroatoms;    -   R₂ is hydrogen, or a substituted or unsubstituted alkyl,        —C(O)-alkyl, —C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl,        monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety;    -   R₃ is hydrogen, or a substituted or unsubstituted alkyl,        —C(O)-alkyl, —C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl,        monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety,        or R₂ and R₃ are joined to form a heterocyclic ring;    -   wherein the dashed line represents a second bond which may be        present or absent, and when present R₃ is oxygen;    -   R₄ and R₅ are each independently substituted or unsubstituted        alkyl, —C(O)-alkyl, —C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl,        monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety,        or    -   R₄NR₅ together form a substituted or unsubstituted monocyclic or        bicyclic, heterocyclic or heteroaryl moiety containing from 1 to        6 heteroatoms;    -   R₁₂ is hydrogen, alkyl, halogen or cyano; and    -   n is 0, 1, 2, 3 or 4,        or an enantiomer, or a specific tautomer, or a pharmaceutically        acceptable salt thereof.

The subject invention also provides compounds having the structure:

wherein

-   -   R₁₀ is substituted or unsubstituted alkyl, —C(O)-alkyl,        —C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, or a substituted or        unsubstituted, monocyclic or bicyclic aryl, heterocyclic or        heteroaryl moiety containing from 1 to 6 heteroatoms; and    -   R₁₁ is a hydrogen or halogen atom.

The subject invention further provided compounds having the structure:

wherein,

-   -   R₁₀ is substituted or unsubstituted alkyl, —C(O)-alkyl,        —C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, or a substituted or        unsubstituted monocyclic or bicyclic aryl, heterocyclic or        heteroaryl moiety containing from 1 to 6 heteroatoms;    -   R₁₁ is a hydrogen or halogen atom; and    -   R₁₂ is hydrogen, alkyl, halogen or cyano.

The subject invention further provides compounds having the structure:

-   -   wherein R_(a) is Cl, Br or I; and    -   R₁₂ is hydrogen, alkyl, halogen or cyano.

The subject invention further provides compounds having the structure:

-   -   wherein R_(b) is hydrogen or methyl.

The subject invention further provides compounds having the structure:

wherein,

-   -   R_(c) is a halogen atom;    -   R₁₁ is a hydrogen or halogen atom; and    -   R₁₂ is hydrogen, alkyl, halogen or cyano.

The subject invention also provides the use of the compound of any oneof Structures I-VIII for manufacturing a medicament useful for treatinga disease associated with the A_(2b) adenosine receptor in a subject,wherein the disease associated with the A_(2b) adenosine receptor isasthma, urticaria, scleroderm arthritis, myocardial infarction,myocardial reperfusion after ischemia, diabetic retinopathy, retinopathyof prematurity, diabetes, diarrhea, inflammatory bowel disease,proliferating tumor or is associated with mast cell degranulation,vasodilation, hypertension, hypersensitivity or the release of allergicmediators.

DETAILED DESCRIPTION

The subject invention provides compounds having the structure:

wherein

-   -   R₁ is substituted or unsubstituted phenyl or a 5-6 membered        heterocyclic or heteroaromatic ring containing from 1 to 5        heteroatoms;    -   R₂ is hydrogen, or a substituted or unsubstituted alkyl,        —C(O)-alkyl, —C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl,        monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety;    -   R₃ is hydrogen, or a substituted or unsubstituted alkyl,        —C(O)-alkyl, —C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl,        monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety,        or R₂ and R₃ are joined to form a heterocyclic ring;    -   wherein the dashed line represents a second bond which may be        present or absent, and when present R₃ is oxygen;    -   R₄ and R₅ are each independently substituted or unsubstituted        alkyl, —C(O)-alkyl, —C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl,        monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety,        or    -   R₄NR₅ together form a substituted or unsubstituted monocyclic or        bicyclic, heterocyclic or heteroaryl moiety containing from 1 to        6 heteroatoms;    -   R₁₂ is hydrogen, alkyl, halogen or cyano; and    -   n is 0, 1, 2, 3 or 4,        or an enantiomer, or a specific tautomer, or a pharmaceutically        acceptable salt thereof.

In one embodiment of Structure I, R₃ is hydrogen, or a substituted orunsubstituted alkyl or aryl.

In another embodiment of Structure I, any heterocyclic or heteroarylring, if present, is a piperazine, piperidine, (1,4)diazepan, pyrazine,pyridine, pyrrolidine, pyrazole, pyrimidine, thiophene, imidazole,azetidine, pyrrole, benzothiazole, benzodioxolane, dithiolane,oxathiine, imidazolidine, quinoline, isoquinoline, dihydroisoquinoline,indole, isoindole, triazaspiro[4.5]decane, morpholine, furan or anisothiazole ring.

In another embodiment, the subject invention provides compounds havingthe structure:

wherein,

-   -   R₆ and R₉ are each, independently, hydrogen or alkyl;    -   R₇ is hydrogen, OH, an alkoxy, an ester, an acetal, a ketal or        CN;    -   R₈ is a substituted or unsubstituted aryl, aryloxy, or        alkylaryl;    -   X is C or N;    -   wherein when X is N, R₇ or R₈ is absent;    -   wherein when X is C, R₇XR₈ may form a 3-8 membered carbocyclic        or heterocyclic ring; and    -   m is 1 or 2.

In one embodiment of Structure II, R₇ is hydrogen, OH, or CN.

In another embodiment, the compound is selected from the groupconsisting of:

-   -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorophenoxy)-piperidin-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorophenoxy)-piperidin-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-methoxybenzyl)-piperidin-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-fluorobenzyl)-piperidin-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin4-yl]-2-[4-(2-chlorobenzyl)-piperidin-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorobenzyl)-piperidin-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorobenzyl)-piperidin-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-benzylpiperazin-1-yl)-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-methoxybenzyl)-piperazin-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-methoxybenzyl)-piperazin-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-methoxybenzyl)-piperazin-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorobenzyl)-piperazin-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorobenzyl)-piperazin-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorobenzyl)-piperazin-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-fluorobenzyl)-piperazine-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-fluorobenzyl)-piperazine-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-trifluoromethylbenzyl)-piperazine-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-cyclohexylmethylpiperazin-1-yl)-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-phenethylpiperazin-1-yl)-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-phenethyl-[1,4]diazepan-1-yl)-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-benzyl-[1,4]diazepan-1-yl)-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4yl]-2-[4-(2-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4yl]-2-[4-(3-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4yl]-2-[4-(4-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4yl]-2-[4-(2-trifluoromethylbenzyl)-[1,4]diazapan-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-trifluoromethylbenzyl)-[1,4]diazepan-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4yl]-2-[4-(4-trifluoromethylbenzyl)-[1,4]diazapan-1-yl]-acetamide;    -   N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4yl]-2-(4-pyridin-3-ylmethyl-[1,4]diazapan-1-yl)-acetamide;    -   N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-[4-(3-chlorobenzyl)-[1,4]diazepan-1-yl]-acetamide;    -   N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-(4-pyridin-2-ylmethyl-[1,4]diazepan-1-yl)-acetamide;    -   N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-[4-(6-methylpyridin-2-ylmethyl)-[1,4]diazepan-1-yl]-acetamide;    -   N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[2-nitro-4-(trifluoromethyl)phenyl]piperazin-1-yl        }acetamide;    -   N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4-tert-butylbenzyl)piperazin-1-yl]acetamide;    -   N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[(2E)-3-phenylprop-2-enyl]piperazin-1-yl}acetamide,        and    -   N-(6-{[2-(acetylamino)ethyl]amino        }-2-phenylpyrimidin-4-yl)-2-(4-benzylpiperidin-1-yl)acetamide.

In another embodiment, the compound isN-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-acetamide.

In a further embodiment, the subject invention provides compounds havingthe structure:

wherein

-   -   R₄ and R₅ are each independently substituted or unsubstituted        alkyl, —C(O)-alkyl, —C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl,        monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety,        or    -   R₄NR₅ together form a substituted or unsubstituted, monocyclic        or bicyclic, heterocyclic or heteroaryl moiety containing from 1        to 6 heteroatoms.

In one embodiment of Structure III,

-   -   R₄ and R₅ are each independently substituted or unsubstituted        alkyl, —C(O)-alkyl, —C(O)-O-alkyl, cycloalkyl, alkenyl,        monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety,        or    -   R₄NR₅ together form a substituted or unsubstituted, monocyclic        or bicyclic, heterocyclic or heteroaryl moiety containing from 1        to 6 heteroatoms.

In another embodiment of Structure III, R₄ and R₅ are each independentlysubstituted or unsubstituted alkyl, —C(O)-alkyl, —C(O)-O-alkyl,cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl orheterocyclic moiety.

In another embodiment, R₄ and R₅ are each independently substituted orunsubstituted alkyl, —C(O)-alkyl, —C(O)-O-alkyl, cycloalkyl, alkenyl,monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety.

In another embodiment, any heterocyclic or heteroaryl ring, if present,is a piperazine, piperidine, (1,4)diazepan, pyrazine, pyridine,pyrrolidine, pyrazole, pyrimidine, thiophene, imidazole, azetidine,pyrrole, benzothiazole, benzodioxolane, dithiolane, oxathiine,imidazolidine, quinoline, isoquinoline, dihydroisoquinoline, indole,isoindole, triazaspiro[4.5]decane, morpholine, furan or an isothiazolering.

The subject invention also provides compounds having the structure:

wherein

-   -   R₁₀ is substituted or unsubstituted alkyl, —C(O)-alkyl,        —C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, or a substituted or        unsubstituted, monocyclic or bicyclic aryl, heterocyclic or        heteroaryl moiety containing from 1 to 6 heteroatoms; and    -   R₁₁ is a hydrogen or halogen atom.

In one embodiment of Structure IV, R₁₀ is a substituted or unsubstitutedalkyl, —C(O)-alkyl, —C(O)-O-alkyl, cycloalkyl, alkenyl, or a substitutedor unsubstituted, monocyclic or bicyclic aryl, heterocyclic orheteroaryl moiety containing from 1 to 6 heteroatoms.

In a further embodiment, R₁₁ is hydrogen.

In a further embodiment, R₁₁ is a halogen atom.

In a further embodiment of Structure IV, any heterocyclic or heteroarylring, if present, is a piperazine, piperidine, (1,4)diazepan, pyrazine,pyridine, pyrrolidine, pyrazole, pyrimidine, thiophene, imidazole,azetidine, pyrrole, benzothiazole, benzodioxolane, dithiolane,oxathiine, imidazolidine, quinoline, isoquinoline, dihydroisoquinoline,indole, isoindole, triazaspiro[4.5]decane, morpholine, furan or anisothiazole ring.

The subject invention further provided compounds having the structure:

wherein,

-   -   R₁₀ is substituted or unsubstituted alkyl, —C(O)-alkyl,        —C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, or a substituted or        unsubstituted monocyclic or bicyclic aryl, heterocyclic or        heteroaryl moiety containing from 1 to 6 heteroatoms;

R₁₁ is a hydrogen or halogen atom; and

R₁₂ is hydrogen, alkyl, halogen or cyano.

In one embodiment of Structure V, R₁₀ is substituted or unsubstitutedalkyl, —C(O)-alkyl, —C(O)-O-alkyl, cycloalkyl, alkenyl, or a substitutedor unsubstituted monocyclic or bicyclic aryl, heterocyclic or heteroarylmoiety containing from 1 to 6 heteroatoms and R₁₂ is hydrogen or methyl.

In a further embodiment, R₁₁ is hydrogen.

In a further embodiment, R₁₂ is hydrogen.

In a further embodiment, R₁₂ is methyl.

In a further embodiment, R₁₁ is a halogen atom.

In a further embodiment, R₁₂ is hydrogen.

In a further embodiment, R₁₂ is methyl.

In a further embodiment, any heterocyclic or heteroaryl ring, ifpresent, is a piperazine, piperidine, (1,4)diazepan, pyrazine, pyridine,pyrrolidine, pyrazole, pyrimidine, thiophene, imidazole, azetidine,pyrrole, benzothiazole, benzodioxolane, dithiolane, oxathiine,imidazolidine, quinoline, isoquinoline, dihydroisoquinoline, indole,isoindole, triazaspiro[4.5]decane, morpholine, furan or an isothiazolering.

The subject invention further provides compounds having the structure:

-   -   wherein R_(a) is Cl, Br or I; and    -   R₁₂ is hydrogen, alkyl, halogen or cyano.

In one embodiment, R_(a) is Cl.

In another embodiment, R_(a) is Br.

The subject invention further provides compounds having the structure:

-   -   wherein R_(b) is hydrogen or methyl.

In one embodiment, R_(b) is hydrogen.

In another embodiment, R_(b) is methyl.

The subject invention further provides compounds having the structure:

wherein,

-   -   R_(c) is a halogen atom;    -   R₁₁ is a hydrogen or halogen atom; and    -   R₁₂ is hydrogen, alkyl, halogen or cyano.

In one embodiment, R_(c) is Cl.

In a further embodiment, R₁₁ is hydrogen.

In another embodiment, R₁₂ is hydrogen.

In another embodiment, R₁₂ is methyl.

In another embodiment, R₁₁ is Cl.

In a further embodiment, R₁₂ is hydrogen.

In another embodiment, R₁₂ is methyl.

In a further embodiment of Structure I,

-   -   R₁ is unsubstituted phenyl or phenyl substituted with Cl;    -   R₂ is hydrogen;    -   R₃ is hydrogen or oxygen;    -   R₄, N, R₅ together form a piperidine ring substituted with        —O(C₆H₅), —O(C₆H₄Cl), —O(C₆H₄[OCH₃]), —(C₆H₅), —CH₂(C₆H₄[OCH₃]),        —CH₂(C₆H₄F), —CH₂(C₆H₄Cl), —(OH)(CH₂)(C₆H₅), —(CN)(C₆H₅),        —(CN)(C₆H₄Cl); a 3,5-dimethyl piperazine ring substituted with        —CH₂(C₆H₅); a piperazine ring substituted with —CH₂(C₆H₅),        —(C₆H₅), —CH₂(C₆H₄[OCH₃]), —CH₂(C₆H₄Cl), —CH₂(C₆H₄F),        —CH₂(C₆H₄[CF₃]), —CH₂(C₅H₄N), —CH₂(C₆H₁₁), —(CH₂)₂(C₆H₅); or a        [1,4]diazepan ring substituted with —(C₆H₅), —(CH₂)₂(C₆H₅),        —CH₂(C₆H₅), —CH₂(C₆H₄F), —CH₂(C₆H₄[CF₃]), —CH₂(C₅H₄N),        —CH₂(C₆H₄Cl), or —CH₂(C₅H₃N[CH₃]); and    -   R₁₂ is hydrogen.

The subject invention also provides a method for treating a diseaseassociated with the A_(2b) adenosine receptor in a subject in need ofsuch treatment comprising administering to the subject a therapeuticallyeffective amount of the compound of Structure I so as to thereby treatthe disease associated with the A_(2b) adenosine receptor in thesubject, wherein the disease associated with the A_(2b) adenosinereceptor is asthma, urticaria, scleroderm arthritis, myocardialinfarction, myocardial reperfusion after ischemia, diabetic retinopathy,retinopathy of prematurity, diabetes, diarrhea, inflammatory boweldisease, proliferating tumor or is associated with mast celldegranulation, vasodilation, hypertension, hypersensitivity or therelease of allergic mediators.

In one embodiment, the disease associated with the A_(2b) adenosinereceptor is diabetes.

In another embodiment, the disease associated with the A_(2b) adenosinereceptor is asthma.

In another embodiment, the disease associated with the A_(2b) adenosinereceptor is associated with mast cell degranulation.

In another embodiment, the disease associated with the A_(2b) adenosinereceptor is a proliferating tumor.

The subject invention also provides a pharmaceutical compositioncomprising the compound of any of Structures I-V and a pharmaceuticallyacceptable carrier.

In one embodiment, the pharmaceutical composition is formulated fororal, topical, parenteral or nasal administration.

The subject invention also provides a process for the manufacture of apharmaceutical composition comprising admixing the compound of any ofStructures I-V with a pharmaceutically acceptable carrier.

The subject invention also provides a package comprising the abovepharmaceutical composition and instructions for use of thepharmaceutical composition in the treatment of a disease associated withthe A_(2b) adenosine receptor.

The subject invention also provides the pharmaceutically acceptable saltof Structure I, wherein the salt is a hydrochloride salt.

The subject invention also provides a process of manufacturing thecompound of Structure VI, comprising the steps of:

-   -   (a) reacting    -    with a 2-substituted diethyl malonate in the presence of a base        in a solvent under suitable conditions to provide:    -   (b) reacting the product of step (a) with a chlorinating agent        to provide:    -   (c) reacting the product of step (b) with an aminating agent in        the presence of solvent to provide:    -   (d) reacting the product of step (c) with        N-acetylethylenediamine to provide:    -   (e) reacting the product with    -    in the presence of base in solvent to provide:    -    wherein R_(a) is Cl or Br; and    -    R₁₂ is hydrogen, alkyl, halogen or cyano.

In one embodiment of the above process, the solvent in step (a) is DMFand the base is DBU.

In another embodiment, the chlorinating agent in step (b) is POCl₃.

In a further embodiment, the aminating agent of step (c) is ammonia andthe solvent is DMSO.

In a further embodiment, the base is 2,6-lutidine and the solvent isCH₂Cl₂/DMF.

In a further embodiment, the subject invention provides a compoundproduced by the above process.

The subject invention also provides a process for manufacturing thecompound of Structure II, comprising reacting a compound having thestructure:

-   -   wherein R_(a) is Cl or Br, with    -    under suitable conditions to provide:

wherein,

-   -   R₆ and R₉ are each independently hydrogen or alkyl;    -   R₇ is hydrogen, OH, an alkoxy, an ester, an acetal, a ketal or        CN;    -   R₈ is a substituted or unsubstituted aryl, aryloxy, or        alkylaryl;    -   X is C or N;    -   wherein when X is N, R₇ or R₈ is absent;    -   wherein when X is C, R₇XR₈ may form a 3-8 membered carbocyclic        or heterocyclic ring; and    -   m is 1 or 2.

The subject invention also provides a compound produced by the aboveprocess.

The subject invention also provides a compound having the structure:

wherein,

-   -   R₁₃ is a substituted or unsubstituted (C₁-C₄)alkyl, branched        alkyl or (C₃-C₇)cycloalkyl, wherein the substituent is —OH, OR,        —NH₂, —NR₁₈R₁₉, —R₂₀NOCR₂₁, R₂₂R₂₃NCO—, carboxyl, carbamoyl        (—R₂₀NOCNR₂₂R₂₃), carbamate (—R₂₀NOCOR), or a heterocyclic ring;        or a substituted or unsubstituted aryl or heterocyclic ring        wherein any substituent, if present, is OH, OR, halogen, NH₂, or        NHR; -wherein R is alkyl, cycloalkyl, aryl, heteroaryl,        susbtituted alkyl, aryl, arylalkyl, or heterocyclic;    -   R₁₄ is substituted or unsubstituted phenyl, wherein the        substituent, if present, is halogen, OH, NH₂, OR, NHR or a 5-6        membered heterocyclic ring;    -   R₁₅ is H, or alkyl;    -   R₁₆ is H, substituted or unsubstituted alkyl or aryl, or R₁₅ and        R₁₆ are joined to form a heterocyclic ring;    -   X is CHR₁₇, CR₂₄R₂₅, O or NR;    -   R₁₇ is H, substituted or unsubstituted alkyl, aryl, arylalkyl,        heterocyclic, heterocyclic alkyl, OH, OR, NH₂, NR₁₈R₁₉,        R₂₀NOCR₂₁, R₂₂R₂₃NCO—, carboxyl, carbamoyl (—R₂₀NOCNR₂₂R₂₃),        carbamate (—R₂₀NOCOR), or (C₃-C₇)cycloalkyl;    -   R₁₈ and R₁₉ are each independently hydrogen, substituted or        unsubstituted alkyl or aryl or R₁₈NR₁₉ together form a        heterocyclic ring of between 4 and 8 members;    -   R₂₀ and R₂₁ are each independently a substituted or        unsubstituted alkyl, aryl, or alkylaryl moiety;    -   R₂₂ and R₂₃ are each independently hydrogen, substituted or        unsubstituted alkyl, aryl or alkylaryl, or R₂₂NR₂₃ together form        a heterocyclic ring of between 4 and 8 members;    -   R₂₄ and R₂₅ are each independently hydrogen, substituted or        unsubstituted alkyl, cycloalkyl, aryl, heterocyclic or R₂₄ and        R₂₅ together form a 3-7 membered ring system or a dioxalane or        dioxane ring system; and    -   p is 0, 1 or 2.

The subject invention also provides the use of the compound of any oneof Structures I-VIII for manufacturing a medicament useful for treatinga disease associated with the A_(2b) adenosine receptor in a subject,wherein the disease associated with the A_(2b) adenosine receptor isasthma, urticaria, scleroderm arthritis, myocardial infarction,myocardial reperfusion after ischemia, diabetic retinopathy, retinopathyof prematurity, diabetes, diarrhea, inflammatory bowel disease,proliferating tumor or is associated with mast cell degranulation,vasodilation, hypertension, hypersensitivity or the release of allergicmediators.

In one embodiment of the above use, the disease associated with theA_(2b) adenosine receptor is diabetes.

In another embodiment, the disease associated with the A_(2b) adenosinereceptor is asthma.

In another embodiment, the disease associated with the A_(2b) adenosinereceptor is associated with mast cell degranulation.

In another embodiment, the disease associated with the A_(2b) adenosinereceptor is a proliferating tumor.

The compound of any one of Structures I-V or IX, wherein any alkyl is astraight chain (C₁-C₃₀)alkyl or a branched chain (C₃-C₃₀)alkyl, anycycloalkyl is (C₃-C₁₀)cycloalkyl, and any substituent, if present, isselected from halogen, hydroxyl, straight chain (C₁-C₃₀)alkyl, branchedchain (C₃-C₃₀)alkyl, (C₃-C₁₀)cycloalkyl, straightchain(C₁-C₃₀)alkylcarbonyloxy, branched chain (C₃-C₃₀)alkylcarbonyloxy,arylcarbonyloxy, straight chain(C₁-C₃₀)alkoxycarbonyloxy, branchedchain(C₃-C₃₀)alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,straight chain(C₁-C₃₀)alkylcarbonyl, branched chain(C₃-C₃₀)alkylcarbonyl, straight chain (C₁-C₃₀)alkoxycarbonyl, branchedchain (C₃-C₃₀)alkoxycarbonyl, aminocarbonyl, straight chain(C₁-C₃₀)alkylthiocarbonyl, branched chain (C₃-C₃₀)alkylthiocarbonyl,straight chain (C₁-C₃₀)alkoxyl, branched chain (C₁-C₃₀)alkoxyl,phosphate, phosphonato, cyano, amino, straight chain (C₁-C₃₀)alkylamino,branched chain (C₃-C₃₀)alkylamino, straight chain (C₁-C₃₀)dialkylamino,branched chain (C₃-C₃₀)dialkylamino, arylamino, diarylamino, straightchain (C₁-C₃₀)alkylarylamino, branched chain (C₃-C₃₀)alkylarylamino,acylamino, straight chain (C₁-C₃₀)alkylcarbonylamino, branched chain(C₃-C₃₀)alkylcarbonylamino, arylcarbonylamino, carbamoyl, ureido,amidino, imino, sulfhydryl, straight chain (C₁-C₃₀)alkylthio, branchedchain (C₃-C₃₀)alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato,sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, 4-10 memberedheterocyclyl, straight chain (C₁-C₃₀)alkylaryl, branched chain(C₃-C₃₀)alkylaryl, or an aromatic or 5-6 membered heteroaromatic moiety,which substituent may be further substituted by any of the above.

This invention also discloses compounds having the structure:

wherein

-   -   R₁₃=Alkyl (1-4 carbons);    -   Branched alkyl substituted with —OH, OR, —NH₂, —NR₁₈R₁₉,        —R₂₀NOCR₂₁, R₂₂R₂₃NCO—, carboxyl, carbamoyl (—R₂₀NOCNR₂₂R₂₃),        carbamate (—R₂₀NOCOR), heterocyclic; Cycloalkyl (3-7 membered);    -   Aryl optionally substituted with OH, OR, halogen, NH₂, NHR;        Heterocyclic (e.g. pyridynyl, imidazole, pyrazole, pyrrole);        wherein R is alkyl, cycloalkyl, aryl, heteroaryl, susbtituted        alkyl, aryl, arylalkyl, or heterocyclic;    -   R₁₄ is phenyl, optionally substituted with halogen, OH, NH₂, OR,        NHR or a 5-6 membered heterocyclic ring;    -   R₁₅ is H, alkyl, R₁₅ joined to R₁₆;    -   R₁₆ is H, alkyl, substituted alkyl, aryl;    -   X is CHR₁₇, CR₂₄R₂₅, O or NR;    -   R₁₇ is H, alkyl, branched alkyl, substituted alkyl, aryl,        substituted aryl, arylalkyl, heterocyclic, heterocyclic alkyl,        OH, OR, NH₂, NR₁₈R₁₉, —R₂₀NOCR₂₁, R₂₂R₂₃NCO—, carboxyl,        carbamoyl (—R₂₀NOCNR₂₂R₂₃), carbamate (—R₂₀NOCOR), cycloalkyl        (3-7 membered);    -   R₁₈ and R₁₉ are each independently hydrogen, substituted or        unsubstituted alkyl or aryl or R₁₈NR₁₉ together form a        heterocyclic ring of between 4 and 8 members;    -   R₂₀ and R₂₁ are each independently a substituted or        unsubstituted alkyl, aryl, or alkylaryl moiety;    -   R₂₂ and R₂₃ are each independently hydrogen, substituted or        unsubstituted alkyl, aryl or alkylaryl, or R₂₂NR₂₃ together form        a heterocyclic ring of between 4 and 8 members;    -   R₂₄ and R₂₅ are each independently hydrogen, substituted or        unsubstituted alkyl, cycloalkyl, aryl, heterocyclic or R₂₄ and        R₂₅ together form a 3-7 membered ring system or a dioxalane or        dioxane ring system; and    -   p is 0, 1 or 2.

The subject invention also includes the specific compounds that areincluded by Structure III, such as compounds 26.1-26.79 discussed in theexamples.

The subject invention also includes the specific compounds that areincluded by Structure IV, such as compounds 29.1-29.146 and 34.1-34.155discussed in the examples.

The subject invention also includes the specific compounds that areincluded by Structure V, such as compounds 36.1-36.141, 41.1-41.144 and46.1-46.82 discussed in the examples.

The subject invention also includes the specific compounds that areincluded by Structure VI, such as compound 6 discussed in the examples.

The subject invention also includes the specific compounds that areincluded by Structure VII, such as compounds 24 and 25 discussed in theexamples.

The subject invention also includes the specific compounds that areincluded by Structure VIII, such as compounds 39 and 44 discussed in theexamples.

The number of carbons when represented as “(C₁-C₃₀)” or “(C₃-C₃₀)” isintended to mean any incremental whole number between 1 and 3 and 30,e.g. 1, 2, 3, 4, 5 . . . or 30.

The present invention is based on compounds which selectively bind toadenosine A_(2b) receptor, thereby treating a disease associated withA_(2b) adenosine receptor in a subject by administering to the subject atherapeutically effective amount of such compounds. The diseases to betreated are associated with, for example, asthma, mast celldegranulation, myocardial reperfusion injury, allergic reactionsincluding but not limited to rhinitis, poison ivy induced responses,urticaria, scleroderm arthritis, autoimmune diseases, inflammatory boweldiseases, hypertension, myocardial infarction, myocardial reperfusionafter ischemia, lymphocyte activation, vasodilation, growth, neuralreflexes in the human gut, retinal angiogenesis, abberantneovascularization such as diabetic retinopathy and retinopathy ofprematurity, modulation of intestinal tone and secretion andneurotransmission and neurosecretion.

A_(2b) receptors have also been implicated in hypersensitivity, hayfever, serum sickness, allergic vasculitis, atopic dermatitis,dermatitis, eczema, idiopathic pulmonary fibrosis, eosinophilicchlorecystitis, chronic airway inflammation, hypereosinophilicsyndromes, eosinophilic gastroenteritis, edema, eosinophilic myocardialdisease, episodic angioedema with eosinophilia, ulcerative colitis,allergic granulomatosis, carcinomatosis, eosinophilic granuloma,familial histiocytosis, tumor, cardiac hypoxia, cerebral ischemia,diuresis, renal failure, neurological disorder, mental disorder,cognitive disorder, myocardial ischemia, bronchoconstriction, Crohn'sdisease, Grave's disease, diabetes, multiple sclerosis, anaemia,psoriasis, fertility disorders, lupus erthyematosus, brain arteriolediameter, the release of allergic mediators, scleroderma, stroke, globalischemia, central nervous system disorder, cardiovascular disorder,renal disorder, inflammatory disorder, gastrointestinal disorder, eyedisorder, allergic disorder, respiratory disorder, or immunologicaldisorder.

The invention further pertains to methods for treating A_(2b) associateddisorders in a mammal by administering to the mammal a therapeuticallyeffective amount of the compounds of the present invention, such thattreatment of the disorder in the mammal occurs.

The invention further pertains to methods for treating A_(2b) associateddisorders in a mammal by administering to the mammal a therapeuticallyeffective amount of the compounds of the present invention, such thattreatment of the disorder in the mammal occurs.

The present invention also pertains to packaged pharmaceuticalcompositions for treating A_(2b) associated disorders. The packagedpharmaceutical composition includes a container holding atherapeutically effective amount of at least one of the compounds of thepresent invention and instructions for using the said compounds fortreating an A_(2b) associated disease.

The compounds of this invention may advantageously be selective A_(2b)receptor antagonists.

In a particularly preferred embodiment, the compound is a water solubleprodrug that is capable of being metabolized in vivo to an active drugby, for example, esterase catalyzed hydrolysis.

In yet another embodiment, the invention features a method forinhibiting the activity of an adenosine receptor (e.g., A_(2b)) in acell, by contacting the cell with a compound of the present invention(e.g., preferably, an adenosine receptor antagonist).

The invention also features a pharmaceutical composition comprising acompound of the present invention. Preferably, the pharmaceuticalpreparation is an ophthalmic formulation (e.g., an periocular,retrobulbar or intraocular injection formulation, a systemicformulation, or a surgical irrigating solution).

The present invention pertains to methods for treating an A_(2b)associated disorder in a mammal. The methods include administration of atherapeutically effective amount of the compounds of the invention,described infra, to the mammal, such that treatment of the A_(2b)associated disorder in the mammal occurs.

The language “treatment of an A_(2b) associated disorder” refers totreatment which includes a significant diminishment of at least onesymptom or effect of the disorder achieved with a compound of theinvention. Typically such disorders are associated with an increase ofadenosine within a host such that the host often experiencesphysiological symptoms which include, but are not limited to, urticaria,scleroderm arthritis, allergic rhinitis, asthma, inflammatory boweldiseases, hypertension, diabetic retinopathy and retinopathy ofprematurity. (See for example, C. E. Muller and B. Stein “AdenosineReceptor Antagonists: Structures and Potential TherapeuticApplications,” Current Pharmaceutical Design, 2:501 (1996) and C. E.Muller “A₁-Adenosine Receptor Antagonists,” Exp. Opin. Ther. Patents7(5):419 (1997) and I. Feoktistove, R. Polosa, S. T. Holgate and I.Biaggioni “Adenosine A_(2B) receptors: a novel therapeutic target inasthma?” TiPS 19; 148 (1998)). The effects often associated with suchsymptoms include, but are not limited to, fever, shortness of breath,nausea, diarrhea, weakness, headache, and even death. In one embodiment,the disorder includes those disease states which are mediated bystimulation of adenosine receptors, e.g., A₁, A_(2a), A_(2b), A₃, etc.,such that calcium concentrations in cells and/or activation of PLC(phospholipase C) is modulated. In a preferred embodiment, the disorderis associated with adenosine receptor(s), e.g., the compound of theinvention acts as an antagonist. Examples of suitable responsive stateswhich can be treated by the compounds of the invention, e.g., adenosinereceptor subtypes which mediate biological effects, include centralnervous system (CNS) effects, cardiovascular effects, renal effects,respiratory effects, immunological effects, gastro-intestinal effectsand metabolic effects. The relative amount of adenosine in a subject canbe associated with the effects listed below; that is increased levels ofadenosine can trigger an effect, e.g., an undesired physiologicalresponse, e.g., an asthmatic attack.

Immunological effects include mast cell degranulation (A_(2b)).Therapeutic applications of antagonists include allergic and nonallergic inflammation, e.g., release of histamine and other inflammatorymediators.

Gastrointestinal effects include colonic, intestinal and diarrhealdisease, e.g., diarrheal disease associated with intestinal inflammation(A_(2b)).

The term “disease state” is intended to include those conditions causedby or associated with unwanted levels of adenosine, adenylyl cyclaseactivity, increased physiological activity associated with aberrantstimulation of adenosine receptors and/or an increase in cAMP. In oneembodiment, the disease state is, for example, asthma, chronicobstructive pulmonary disease, allergic rhinitis, bronchitis, renaldisorders, gastrointestinal disorders, or eye disorders. Additionalexamples include chronic bronchitis and cystic fibrosis. Suitableexamples of inflammatory diseases include non-lymphocytic leukemia,myocardial ischaemia, angina, infarction, cerebrovascular ischaemia,intermittent claudication, critical limb ischemia, venous hypertension,varicose veins, venous ulceration and arteriosclerosis. Impairedreperfusion states include, for example, any post-surgical trauma, suchas reconstructive surgery, thrombolysis or angioplasty.

This invention also provides a combination therapy for glaucoma,comprising one of the compounds of the invention, and a prostagladinagonist, beta-2 agonist, or a muscarinic antagonist.

The language “treating an A_(2b) associated disorder” or “treating anA_(2b) associated disease” is intended to include changes in a diseasestate or condition, as described above, such that physiological symptomsin a mammal can be significantly diminished or minimized. The languagealso includes control, prevention or inhibition of physiologicalsymptoms or effects associated with an aberrant amount of adenosine. Inone preferred embodiment, the control of the disease state or conditionis such that the disease state or condition is eradicated. In anotherpreferred embodiment, the control is selective such that aberrant levelsof adenosine receptor activity are controlled while other physiologicsystems and parameters are unaffected.

The language “therapeutically effective amount” of the compounds of theinvention, described infra, refers to that amount of a therapeuticcompound necessary or sufficient to perform its intended function withina mammal, e.g., treat an A_(2b) associated disorder, or a disease statein a mammal. An effective amount of the therapeutic compound can varyaccording to factors such as the amount of the causative agent alreadypresent in the mammal, the age, sex, and weight of the mammal, and theability of the therapeutic compounds of the present invention to affectthe A_(2b) associated disorder in the mammal. One of ordinary skill inthe art would be able to study the aforementioned factors and make adetermination regarding the effective amount of the therapeutic compoundwithout undue experimentation.

An in vitro or in vivo assay also can be used to determine an “effectiveamount” of the therapeutic compounds described infra. The ordinarilyskilled artisan would select an appropriate amount of the therapeuticcompound for use in the aforementioned assay or as a therapeutictreatment.

A therapeutically effective amount preferably diminishes at least onesymptom or effect associated with the A_(2b) associated disorder beingtreated by at least about 20%, (more preferably by at least about 40%,even more preferably by at least about 60%, and still more preferably byat least about 80%) relative to untreated subjects. Assays can bedesigned by one skilled in the art to measure the diminishment of suchsymptoms and/or effects. Any art recognized assay capable of measuringsuch parameters are intended to be included as part of this invention.For example, if asthma is the state being treated, then the volume ofair expended from the lungs of a subject can be measured before andafter treatment for measurement of increase in the volume using an artrecognized technique. Likewise, if inflammation is the state beingtreated, then the area which is inflamed can be measured before andafter treatment for measurement of diminishment in the area inflamedusing an art recognized technique.

The term “cell” includes both prokaryotic and eukaryotic cells.

The term “animal” includes any organism with adenosine receptors.Examples of animals include yeast, mammals, reptiles, and birds. It alsoincludes transgenic animals.

The term “mammal” is art recognized and is intended to include ananimal, more preferably a warm-blooded animal, most preferably cattle,sheep, pigs, horses, dogs, cats, rats, mice, and humans. Mammalssusceptible to A_(2b) associated disorders responsive state,inflammation, emphysema, asthma, central nervous system conditions, oracute respiratory distress syndrome, for example, are included as partof this invention.

In another aspect, the present invention pertains to methods formodulating an adenosine receptor(s) in a mammal by administering to themammal a therapeutically effective amount of the compounds of theinvention, such that modulation of the adenosine receptor in the mammaloccurs. Suitable adenosine receptors include the families of A₁, A₂, orA₃. In a preferred embodiment, the compound is an adenosine receptorantagonist.

The language “modulating an adenosine receptor” is intended to includethose instances where a compound interacts with an adenosinereceptor(s), causing increased, decreased or abnormal physiologicalactivity associated with an adenosine receptor or subsequent cascadeeffects resulting from the modulation of the adenosine receptor.Physiological activities associated with adenosine receptors includeinduction of sedation, vasodilation, suppression of cardiac rate andcontractility, inhibition of platelet aggregbility, stimulation ofgluconeogenesis, inhibition of lipolysis, opening of potassium channels,reducing flux of calcium channels, etc.

The terms “modulate”, “modulating” and “modulation” are intended toinclude preventing, eradicating, or inhibiting the resulting increase ofundesired physiological activity associated with abnormal stimulation ofan adenosine receptor, e.g., in the context of the therapeutic methodsof the invention. In another embodiment, the term modulate includesantagonistic effects, e.g., diminishment of the activity or productionof mediators of allergy and allergic inflammation which results from theoverstimulation of adenosine receptor(s). For example, the therapeuticdeazapurines of the invention can interact with an adenosine receptor toinhibit, for example, adenylate cyclase activity.

The language “condition characterized by aberrant adenosine receptoractivity” is intended to include those diseases, disorders or conditionswhich are associated with aberrant stimulation of an adenosine receptor,in that the stimulation of the receptor causes a biochemical and orphysiological chain of events that is directly or indirectly associatedwith the disease, disorder or condition. This stimulation of anadenosine receptor does not have to be the sole causative agent of thedisease, disorder or condition but merely be responsible for causingsome of the symptoms typically associated with the disease, disorder, orcondition being treated. The aberrant stimulation of the receptor can bethe sole factor or at least one other agent can be involved in the statebeing treated. Examples of conditions include those disease stateslisted supra, and those symptoms manifested by the presence of increasedadenosine receptor activity.

The language “treating or treatment of a condition characterized byaberrant adenosine receptor activity” is intended to include thealleviation of or diminishment of at least one symptom typicallyassociated with the condition. The treatment also includes alleviationor diminishment of more than one symptom. Preferably, the treatmentcures, e.g., substantially eliminates, the symptoms associated with thecondition.

The invention further pertains to a method for inhibiting the activityof an adenosine receptor (e.g., an A_(2b) adenosine receptor) in a cellby contacting the cell with a compound of the invention. Preferably, thecompound is an antagonist of the receptor.

In another embodiment, the invention relates to a pharmaceuticalcomposition containing a compound of the invention and apharmaceutically acceptable carrier.

The invention also pertains to a method for treating an A_(2b)associated disease in an animal, by administering to a mammal atherapeutically effective amount of a compound of the invention, suchthat treatment of the A_(2b) associated disorder occurs. Advantageously,the disease state may be a disorder mediated by adenosine. Examples ofpreferred disease states include: central nervous system disorders,cardiovascular disorders, renal disorders, inflammatory disorders,allergic disorders, gastrointestinal disorders, eye disorders, andrespiratory disorders.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, andcycloalkyl substituted alkyl groups. In preferred embodiments, astraight chain or branched chain alkyl has 30 or fewer carbon atoms inits backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ for branchedchain), and more preferably 20 or fewer. Likewise, preferred cycloalkylshave from 4-10 carbon atoms in their ring structure, and more preferablyhave 5, 6 or 7 carbons in the ring structure.

The term “substituted alkyls” refers to alkyl moieties havingsubstituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example,halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,phosphinato, cyano, amino (including alkyl amino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Itwill be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate. Cycloalkyls can be further substituted, e.g., with thesubstituents described above. An “alkylaryl” moiety is an alkylsubstituted with an aryl (e.g., phenylmethyl (benzyl)). The term “alkyl”also includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double or triple bond respectively.

The term “aryl” as used herein, refers to the radical of aryl groups,including 5- and 6-membered single-ring aromatic groups that may includefrom zero to four heteroatoms, for example, benzene, pyrrole, furan,thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole,pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.Aryl groups also include polycyclic fused aromatic groups such asnaphthyl, quinolyl, indolyl, and the like. Those aryl groups havingheteroatoms in the ring structure may also be referred to as “arylheterocycles”, “heteroaryls” or “heteroaromatics”. The aromatic ring canbe substituted at one or more ring positions with such substituents asdescribed above, as for example, halogen, hydroxyl, alkoxy,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino (including alkyl amino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Arylgroups can also be fused or bridged with alicyclic or heterocyclic ringswhich are not aromatic so as to form a polycycle (e.g., tetralin).

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double or triple bond respectively.For example, the invention contemplates cyano and propargyl groups.

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto ten carbons, more preferably from one to six carbon atoms in itsbackbone structure, even more preferably one to three carbon atoms inits backbone structure. Likewise, “lower alkenyl” and “lower alkynyl”have similar chain lengths.

The terms “alkoxyalkyl”, “polyaminoalkyl” and “thioalkoxyalkyl” refer toalkyl groups, as described above, which further include oxygen, nitrogenor sulfur atoms replacing one or more carbons of the hydrocarbonbackbone, e.g., oxygen, nitrogen or sulfur atoms.

The terms “polycyclyl” or “polycyclic radical” refer to the radical oftwo or more cyclic rings (e.g., cycloalkyls, cycloalkenyls,cycloalkynyls, aryls and/or heterocyclyls) in which two or more atomsare common to two adjoining rings, e.g., the rings are “fused rings”.Rings that are joined through non-adjacent atoms are termed “bridged”rings. Each of the rings of the polycycle can be substituted with suchsubstituents as described above, as for example, halogen, hydroxyl,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,phosphinato, cyano, amino (including alkyl amino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen,sulfur and phosphorus.

The term “heterocycle” or “heterocyclic system” as used herein isintended to mean a stable 5, 6 or 7-membered monocyclic or 7, 8, 9, 10or 11-membered bicyclic heterocyclic ring which is saturated orpartially unsaturated.

The terms “carbocyclic” or “heterocyclic” further include spirocompounds, which denote a bicyclic compound in which the two rings haveone atom in common and the atom may be carbon or a heteroatom.

The term “amino acids” includes naturally and unnaturally occurringamino acids found in proteins such as glycine, alanine, valine,cysteine, leucine, isoleucine, serine, threonine, methionine, glutamicacid, aspartic acid, glutamine, asparagine, lysine, arginine, proline,histidine, phenylalanine, tyrosine, and tryptophan. Amino acid analogsinclude amino acids with lengthened or shortened side chains or variantside chains with appropriate functional groups. Amino acids also includeD and L stereoisomers of an amino acid when the structure of the aminoacid admits of stereoisomeric forms. The term “dipeptide” includes twoor more amino acids linked together. Preferably, dipeptides are twoamino acids linked via a peptide linkage. Particularly preferreddipeptides include, for example, alanine-alanine and glycine-alanine.

It will be noted that the structure of some of the compounds of thisinvention includes asymmetric carbon atoms and thus occur as racematesand racemic mixtures, single enantiomers, diastereomeric mixtures andindividual diastereomers. All such isomeric forms of these compounds areexpressly included in this invention. Each stereogenic carbon may be ofthe R or S configuration. It is to be understood accordingly that theisomers arising from such asymmetry (e.g., all enantiomers anddiastereomers) are included within the scope of this invention, unlessindicated otherwise. Each specific isomer can be obtained insubstantially pure form by classical separation techniques and/or bystereochemically controlled synthesis.

The invention further pertains to pharmaceutical compositions fortreating A_(2b) associated disorders in a mammal. The pharmaceuticalcomposition includes a therapeutically effective amount of a compound ofthe invention and a pharmaceutically acceptable carrier. It is to beunderstood, that all of the compounds described below are included fortherapeutic treatment. It is to be further understood that the compoundsof the invention can be used alone or in combination with othercompounds of the invention or in combination with additional therapeuticcompounds, such as antibiotics, antiinflammatories, or anticanceragents, for example.

The term “antibiotic” is art recognized and is intended to include thosesubstances produced by growing microorganisms and synthetic derivativesthereof, which eliminate or inhibit growth of pathogens and areselectively toxic to the pathogen while producing minimal or nodeleterious effects upon the infected host subject. Suitable examples ofantibiotics include, but are not limited to, the principle classes ofaminoglycosides, cephalosporins, chloramphenicols, fuscidic acids,macrolides, penicillins, polymixins, tetracyclines and streptomycins.

The term “antiinflammatory” is art recognized and is intended to includethose agents which act on body mechanisms, without directly antagonizingthe causative agent of the inflammation such as glucocorticoids,aspirin, ibuprofen, NSAIDS, etc.

The term “anticancer agent” is art recognized and is intended to includethose agents which diminish, eradicate, or prevent growth of cancercells without, preferably, adversely affecting other physiologicalfunctions. Representative examples include cisplatin andcyclophosphamide.

The term “cancer” as used herein is intended to mean a cellularmalignancy whose unique trait—loss of normal controls—results inunregulated growth, lack of differentiation, and ability to invade localtissues and metastasize. The presence of a cellular malignancy is oftenindicated by the presence of a tumor. Local tissue invasion can resultfrom local tumor pressure on normal tissues that can lead toinflammation, or the tumor may elaborate substances that lead toenzymatic destruction.

When the compounds of the present invention are administered aspharmaceuticals, to humans and mammals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99.5% (morepreferably, 0.5 to 90%) of active ingredient in combination with apharmaceutically acceptable carrier.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting a compound(s) of thepresent invention within or to the subject such that it can performs itsintended function. Typically, such compounds are carried or transportedfrom one organ, or portion of the body, to another organ, or portion ofthe body. Each carrier must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the patient. Some examples of materials which can serve aspharmaceutically acceptable carriers include: sugars, such as lactose,glucose and sucrose; starches, such as corn starch and potato starch;cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; powdered tragacanth; malt;gelatin; talc; excipients, such as cocoa butter and suppository waxes;oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; glycols, such as propylene glycol;polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;esters, such as ethyl oleate and ethyl laurate; agar; buffering agents,such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol;phosphate buffer solutions; and other non-toxic compatible substancesemployed in pharmaceutical formulations.

As set out above, certain embodiments of the present compounds cancontain a basic functional group, such as amino or alkylamino, and are,thus, capable of forming pharmaceutically acceptable salts withpharmaceutically acceptable acids. The term “pharmaceutically acceptablesalts” in this respect, refers to the relatively non-toxic, inorganicand organic acid addition salts of compounds of the present invention.These salts can be prepared in situ during the final isolation andpurification of the compounds of the invention, or by separatelyreacting a purified compound of the invention in its free base form witha suitable organic or inorganic acid, and isolating the salt thusformed. Representative salts include the hydrobromide, hydrochloride,sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate,palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate,glucoheptonate, lactobionate, and laurylsulphonate salts and the like.(See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19).

In other cases, the compounds of the present invention may contain oneor more acidic functional groups and, thus, are capable of formingpharmaceutically acceptable salts with pharmaceutically acceptablebases. The term “pharmaceutically acceptable salts” in these instancesrefers to the relatively non-toxic, inorganic and organic base additionsalts of compounds of the present invention. These salts can likewise beprepared in situ during the final isolation and purification of thecompounds, or by separately reacting the purified compound in its freeacid form with a suitable base, such as the hydroxide, carbonate orbicarbonate of a pharmaceutically acceptable metal cation, with ammonia,or with a pharmaceutically acceptable organic primary, secondary ortertiary amine. Representative alkali or alkaline earth salts includethe lithium, sodium, potassium, calcium, magnesium, and aluminum saltsand the like. Representative organic amines useful for the formation ofbase addition salts include ethylamine, diethylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine and the like.

The term “pharmaceutically acceptable esters” refers to the relativelynon-toxic, esterified products of the compounds of the presentinvention. These esters can be prepared in situ during the finalisolation and purification of the compounds, or by separately reactingthe purified compound in its free acid form or hydroxyl with a suitableesterifying agent. Carboxylic acids can be converted into esters viatreatment with an alcohol in the presence of a catalyst. Hydroxylcontaining derivatives can be converted into esters via treatment withan esterifying agent such as alkanoyl halides. The term is furtherintended to include lower hydrocarbon groups capable of being solvatedunder physiological conditions, e.g., alkyl esters, methyl, ethyl andpropyl esters. (See, for example, Berge et al., supra.)

The invention further contemplates the use of prodrugs which areconverted in vivo to the therapeutic compounds of the invention (see,e.g., R. B. Silverman, 1992, “The Organic Chemistry of Drug Design andDrug Action”, Academic Press, Chapter 8). Such prodrugs can be used toalter the biodistribution (e.g., to allow compounds which would nottypically enter the reactive site of the protease) or thepharmacokinetics of the therapeutic compound. For example, a carboxylicacid group, can be esterified, e.g., with a methyl group or an ethylgroup to yield an ester. When the ester is administered to a subject,the ester is cleaved, enzymatically or non-enzymatically, reductively orhydrolytically, to reveal the anionic group. An anionic group can beesterified with moieties (e.g., acyloxymethyl esters) which are cleavedto reveal an intermediate compound which subsequently decomposes toyield the active compound. In another embodiment, the prodrug is areduced form of a sulfate or sulfonate, e.g., a thiol, which is oxidizedin vivo to the therapeutic compound. Furthermore, an anionic moiety canbe esterified to a group which is actively transported in vivo, or whichis selectively taken up by target organs. The ester can be selected toallow specific targeting of the therapeutic moieties to particularreactive sites, as described below for carrier moieties.

The compounds of the invention may comprise water-soluble prodrugs whichare described in WO 99/33815, International Application No.PCT/US98/04595, filed Mar. 9, 1998 and published Jul. 8, 1999. Theentire content of WO 99/33815 is expressly incorporated herein byreference. The water-soluble prodrugs are metabolized in vivo to anactive drug, e.g., by esterase catalyzed hydrolysis.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willgenerally be that amount of the compound which produces a therapeuticeffect. Generally, out of one hundred percent, this amount will rangefrom about 1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol, and/or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as, for example,acetyl alcohol and glycerol monostearate; absorbents, such as kaolin andbentonite clay; lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and coloring agents. In the case of capsules, tabletsand pills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert dilutents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert dilutents, the oral compositions can also includeadjuvants such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the activecompound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.Preferably, the pharmaceutical preparation is an ophthalmic formulation(e.g., an periocular, retrobulbar or intraocular injection formulation,a systemic formulation, or a surgical irrigating solution).

The ophthalmic formulations of the present invention may include one ormore of the compounds of the invention and a pharmaceutically acceptablevehicle. Various types of vehicles may be used. The vehicles willgenerally be aqueous in nature. Aqueous solutions are generallypreferred, based on case of formulation, as well as a patient's abilityto easily administer such compositions by means of instilling one to twodrops of the solutions in the affected eyes. However, the deazapurinesof the present invention may also be readily incorporated into othertypes of compositions, such as suspensions, viscous or semi-viscous gelsor other types of solid or semi-solid compositions. The ophthalmiccompositions of the present invention may also include various otheringredients, such as buffers, preservatives, co-solvents and viscositybuilding agents.

An appropriate buffer system (e.g., sodium phosphate, sodium acetate orsodium borate) may be added to prevent pH drift under storageconditions.

Ophthalmic products are typically packaged in multidose form.Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: benzalkonium chloride,thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethylalcohol, edetate disodium, sorbic acid, polyquaternium-1, or otheragents known to those skilled in the art. Such preservatives aretypically employed at a level of from 0.001 to 1.0% weight/volume (“%w/v”).

When the compounds of the present invention are administered duringintraocular surgical procedures, such as through retrobulbar orperiocular injection and intraocular perfusion or injection, the use ofbalanced salt irrigating solutions as vehicles are most preferred. BSS®Sterile Irrigating Solution and BSS Plus® Sterile Intraocular IrrigatingSolution (Alcon Laboratories, Inc., Fort Worth, Tex., USA) are examplesof physiologically balanced intraocular irrigating solutions. The lattertype of solution is described in U.S. Pat. No. 4,550,022 (Garabedian, etal.), the entire contents of which are hereby incorporated in thepresent specification by reference. Retrobulbar and periocularinjections are known to those skilled in the art and are described innumerous publications including, for example, Ophthalmic Surgery:Principles of Practice, Ed., G. L. Spaeth. W. B. Sanders Co.,Philadelphia, Pa., U.S.A., pages 85-87 (1990).

As indicated above, use of the compounds of the present invention toprevent or reduce damage to retinal and optic nerve head tissues at thecellular level is a particularly important aspect of one embodiment ofthe invention. Ophthalmic conditions which may be treated include, butare not limited to, retinopathies and damage associated with injuries toophthalmic tissues, such as ischemia reperfusion injuries. The compoundsmay be used for acute treatment of temporary conditions, or may beadministered chronically, especially in the case of degenerativedisease. The compounds may also be used prophylactically, especiallyprior to ocular surgery or noninvasive ophthalmic procedures, or othertypes of surgery.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given by formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administration is preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systematically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, intravenous andsubcutaneous doses of the compounds of this invention for a patient,when used for the indicated analgesic effects, will range from about0.0001 to about 200 mg per kilogram of body weight per day, morepreferably from about 0.01 to about 150 mg per kg per day, and stillmore preferably from about 0.2 to about 140 mg per kg per day.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical composition.

The present invention also pertains to packaged pharmaceuticalcompositions for treating A_(2b) associated disorders in a mammal. Thepackaged pharmaceutical compositions include a container holding atherapeutically effective amount of at least one compound of theinvention, as described below, and instructions for using the compoundfor treating the A_(2b) associated disorder in the mammal.

In another aspect, the invention features a method for treating damageto the eye of an animal (e.g., a human) by administering to the animalan effective amount of the compounds of the present invention.Preferably, the compound is an antagonist of A_(2b) adenosine receptorsin cells of the animal. The damage is to the retina or the optic nervehead and may be acute or chronic. The damage may be the result of, forexample, glaucoma, edema, ischemia, hypoxia or trauma.

The invention further pertains to a method for inhibiting the activityof an adenosine receptor (e.g., an A_(2b) adenosine receptor) in a cellby contacting the cell with a compound of the invention. Preferably, thecompound is an antagonist of the receptor.

In another embodiment, the invention relates to a pharmaceuticalcomposition containing a compound of the invention and apharmaceutically acceptable carrier.

The invention also pertains to a method for treating an A_(2b)associated disease state in an animal, by administering to a mammal atherapeutically effective amount of a compound of the invention, suchthat treatment of disorder in the animal occurs. Advantageously, thedisease state may be a disorder mediated by adenosine. Examples ofpreferred disease states include: central nervous system disorders,cardiovascular disorders, renal disorders, inflammatory disorders,allergic disorders, gastrointestinal disorders, eye disorders, andrespiratory disorders.

The invention further pertains to pharmaceutical compositions fortreating an A_(2b) associated disease state in a mammal, e.g.,respiratory disorders (e.g., asthma, bronchitis, chronic obstructivepulmonary disorder, and allergic rhinitis), renal disorders,gastrointestinal disorders, and eye disorders. The pharmaceuticalcomposition includes a therapeutically effective amount of a compound ofthe invention, described below, and a pharmaceutically acceptablecarrier. It is to be understood, that all of the compounds describedbelow are included for therapeutic treatment. It is to be furtherunderstood that the compounds of the invention can be used alone or incombination with other compounds of the invention or in combination withadditional therapeutic compounds, such as antibiotics,antiinflammatories, or anticancer agents, for example.

As indicated above, use of the compounds of the invention to prevent orreduce damage to retinal and optic nerve head tissues at the cellularlevel is a particularly important aspect of one embodiment of theinvention. Ophthalmic conditions which may be treated include, but arenot limited to, retinopathies, macular degeneration, ocular ischemia,glaucoma, and damage associated with injuries to ophthalmic tissues,such as ischemia reperfusion injuries, photochemical injuries, andinjuries associated with ocular surgery, particularly injuries to theretina or optic nerve head by exposure to light or surgical instruments.The compounds may also be used as an adjunct to ophthalmic surgery, suchas by vitreal or subconjunctival injection following ophthalmic surgery.The compounds may be used for acute treatment of temporary conditions,or may be administered chronically, especially in the case ofdegenerative disease. The compounds may also be used prophylactically,especially prior to ocular surgery or noninvasive ophthalmic procedures,or other types of surgery.

The features and other details of the invention will now be moreparticularly described and pointed out in the claims. It is to beunderstood that the particular embodiments of the invention are shown byway of illustration and not as limitations of the invention. Theprincipal features of this invention can be employed in variousembodiments without departing from the scope of the invention.

The invention is further illustrated by the following examples which inno way should be construed as being further limiting. The contents ofall references, pending patent applications and published patentapplications, cited throughout this application, including thosereferenced in the background section, are hereby incorporated byreference. It should be understood that the models used throughout theexamples are accepted models and that the demonstration of efficacy inthese models is predictive of efficacy in humans.

This invention will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the claims which followthereafter.

EXPERIMENTAL DETAILS

General Information

LC/MS analysis was performed using a Gilson 215 autosampler and Gilson819 autoinjector, attached to a Hewlett Packard HP110.

Mass spectra were obtained on a Micromass Platform II mass spectrometer,using positive electrospray ionization.

LC analysis was undertaken at 254 nm using a UV detector. Samples wereeluted on a Phenomenex Luna C18(2) (5 microns, 4.6×150 mm) column usingeither a linear gradient of 15-99% solvent A in solvent B over 10minutes (method A, non-polar) or 5-100% solvent A in solvent B over 15minutes (method B, polar). The solvent A was 100% acetonitrile, solventB was 0.01% formic acid, which was observed to have no noticeable effecton sample retention time, in water.

IR spectra were recorded on a Perkin-Elmer Spectrum 1000 FT-IRspectrometer as thin films using diffuse reflectance.

¹H NMR and ¹³C NMR spectra were recorded with Varian instruments (400MHz or 200 MHz for ¹H, 100.6 MHz or 50.3 MHz for ¹³C) at ambienttemperature with TMS or the residual solvent peak as internal standards.The line positions or multiplets are given in ppm (δ) and the couplingconstants (J) are given as absolute values in Hertz, while the signalmultiplicities are abbreviated as follows: s (singlet), d (doublet), t(triplet), q (quartet), quint (quintet), m (multiplet), m, (centeredmultiplet), br (broadened).

All melting points were determined with a Mel-Temp II apparatus and areuncorrected.

Elemental analyses were carried out at Atlantic Microlab, Inc.,Norcross, Ga.

Commercially available anhydrous solvents and HPLC-grade solvents wereused without further purification.

Abbreviations:

-   -   DMSO Dimethylsulfoxide    -   HATU O-(7-Azabenzotriazolo-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   HPLC High Pressure Liquid Chromatography    -   LCMS Liquid Chromatography/Mass Spectrometry    -   NMP N-Methylpyrrolidinone    -   NMR Nuclear Magnetic Resonance    -   PS-NCO Polymer Supported Isocyanate    -   RT Retention Time    -   SCX Strong cation exchange silica    -   THF Tetrahydrofuran        Details for Experimental Procedures of Discrete Examples

Reverse phase, high pressure liquid chromatography where mentioned belowin the following preparations was effected according to the followinggeneral method. A Xterra column (C18 silica packing, 7 micron particlesize, 19×150 mm) was previously equilibriated in a mixture of water,acetonitrile, and trifluoroacetic acid (90:10:0.1 v/v/v) at pH 3.0.Samples were eluted using a linear gradient of 10% to 90% acetonitrilein water, containing 0.1% trifluoroacetic acid, at pH 3.0, over 10minutes, with a flow rate of 10 mLmin⁻¹. Analysis was undertaken at 220nm using a diode array detector. Where a compound was purified in thismanner it was assumed to be isolated as its trifluoroacetate salt.

Purification using benzenesulphonic acid functionalised strong cationexchange (SCX) silica in a 96 well format, where mentioned below in thefollowing preparations, was effected according to the following generalmethod. Approximately 70 mg of the silica per well was conditioned with500 μl of a 1:1 v/v methanol water mixture. The impure material wasloaded as a 4:1 mixture of 0.1M HCl:NMP then washed with 500 μlmethanol. Purified material was eluted with 500 μl of a 3:97 v/v mixtureof ammonium hydroxide:methanol.

Analytical Procedures

¹H NMR analysis was conducted on a Varian Gemini instrument at 400 MHz,using standard procedures.

LCMS analysis was performed using a Gilson 215 autosampler and Gilson819 autoinjector, attached to a Hewlett Packard HP110. Mass spectra wereobtained on a Micromass Platform LC mass spectrometer, using positiveand negative electrospray ionisation. Masses found refer to the mostabundant MH⁺ positive ion found corresponding to the title compoundunless otherwise stated. Analysis was undertaken at 220 nm using a diodearray detector.

The following general methods were used:

-   -   Method A: Waters Symmetry C18 (3.5 micron, 2.1×30 mm), 4.8        minute gradient or    -   Method B: Phenomenex Mercury MS Luna C18 (3 micron, 2.0×10 mm),        3.6 minute gradient

Samples were eluted using a linear gradient of 0-100% Solvent B inSolvent A over either 4.8 or 3.6 minutes (see above). The buffer usedwas formic acid (0.1%) which was observed to have had no noticeableeffect on sample retention time.

Mobile Phase (plus buffer)

-   -   Solvent A: Water (95%), acetonitrile (5%).    -   Solvent B: Acetonitrile (100%).

EXAMPLE 1

Synthesis of Chloroacetamide Intermediate 6.

Condensation of benzamidine hydrochloride with diethyl malonate in DMFusing DBU as base gave the diol 2, which was converted to the dichloride3 by reaction with neat POCl₃. Selective, stepwise displacement of thechloro substituents with ammonia in DMSO and then with neatN-acetylethylenediamine yielded the diamine 5. Acylation withchloroacetyl chloride using 2,6-lutidine as base in CH₂Cl₂/DMF 12:1 gavethe chloroacetamide 6.

2-Phenylpyrimidine-4,6-diol (2): A solution of benzamidine hydrochloride(44.41 g; 0.284 mol), diethyl malonate (45.51 g; 0.284 mol) and DBU(86.40 g; 0.568 mol) in DMF (250 mL) was heated at 85° C. for 20 h.After cooling to room temperature, the flask was placed in arefrigerator overnight. The crystalline product was collected byfiltration and washed with DMF (300 mL), then dissolved in water (ca.110 mL) and acidified with 2 M HCl (110 mL) with water added, asnecessary, to maintain a suspension. The product was collected byfiltration, washed with water (100 mL) and dried to a constant weightunder high vacuum giving 39.09 g (73%) of an off-white solid. LC (methodB) t_(R)=6.2 min; ¹H NMR (200 MHz, DMSO-d₆) δ 8.08 (m, 2H), 7.54 (m,3H), 5.34 (s, 1H); ESIMS 189.0 ([M+H]⁺).

4,6-Dichloro-2-phenylpyrimidine (3): A slurry of diol 2 (39.08 g; 0.208mol) in phosphorus oxychloride (124 mL; 1.33 mol) was heated from75-120° C. over 45 min. After 20 h at 120° C. the volatiles were removedin vacuo. The resulting tan solid was added to crushed ice (600 mL) andthis suspension was stirred for 2 h at rt, collected by filtration,washed with water and dried to a constant weight under high vacuumgiving a tan solid (44.34 g; 95%). ¹H NMR (200 MHz, CDCl₃) δ 8.44 (m,2H), 7.51 (m, 3H), 7.27 (s, 1H).

6-Chloro-2-phenylpyrimidin-4-ylamine (4): An ice-cold suspension ofpyrimidine 3 (44.34 g; 0.197 mol) in DMSO (366 mL) was saturated withammonia, during which time a solution formed. After 24 h at rt, water(710 mL) was added dropwise. The suspension was cooled in an ice bathfor 1 h then collected by filtration and washed with water (500 mL),yielding a light tan powder after drying in vacuo (37.84 g; 93%). LC(method B) t_(R)=16.0 min; ¹H NMR (200 MHz, CDCl₃) δ 8.33 (m, 2H), 8.44(m, 3H), 6.32 (s, 1H), 5.12 (brs, 2H); ¹³C NMR (50.3 MHz, CDCl₃) δ165.1, 164.0, 160.5, 136.7, 131.0, 128.4, 128.4, 101.4; ESIMS205.9/207.8 (100/34) [MH⁺].

N-[2-(6-Amino-2-phenylpyrimidin-4-ylamino)-ethyl]-acetamide (5): Asolution of chloroarene 4 (20.57 g; 0.100 mol) inN-(2-aminoethyl)-acetamide (71.05 g; 0.696 mol) was heated from 60 to120° C. over 20 min then kept at 120° C. for 4.0 h. After cooling to rt,the reaction was diluted with EtOAc (500 mL) then washed with water(1×150 mL). The aq phase was extracted with EtOAc (3×25 mL) and thecombined organic portions were washed with water (2×25 mL) and saturatedNaCl (2×50 mL). The solution was dried (MgSO₄), filtered thenconcentrated in vacuo to 21.34 g of an off-white hard foam. The productwas purified in two batches on silica gel (1.7 L total) using 15-8:1DCM:MeOH yielding a hard white foam (15.36 g; 57%). LC (method B)t_(R)=5.5 min; ¹H NMR (200 MHz, CDCl₃) δ 8.29 (m, 2H), 7.43 (m, 3H),6.71 (brs, 1H), 5.41 (s, 1H), 5.12 (brt, J=5.4 Hz, 1H), 4.68 (brs, 2H),3.53 (m, 1H), 3.45 (m, 1H), 1.83 (s, 3H); ESIMS 272.03 (100) [MH⁺].

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-chloroacetamide(6): A solution of amine 5 was titrated with chloroacetyl chloride withmonitoring by TLC (SiO₂/8:1 and 14:1 DCM:MeOH) as follows: Neatchloroacetyl chloride (0.45 mL; 5.7 mmol) was slowly added down the sideof a flask immersed in an ice-water bath into a solution ofaminopyrimidine 5 (1.531 g; 5.64 mmol) and 2,6-lutidine (2.0 mL; 17mmol) in DCM (30 mL) plus DMF (2.5 mL). Starting material remained soadditional chloroacetyl chloride was added after 0.4 h (0.45 mL; 5.7mmol) and again after an additional 0.5 h (90 μL; 1.1 mmol). After 0.5h, EtOAc (150 mL) was added and the solution washed with saturatedNaHCO₃ (40 mL), 50% saturated NaCl (5×40 mL), saturated NaCl (2×40 mL),dried (MgSO₄), filtered and concentrated to a yellow-orange crystallinesolid. The crude material was triturated with hexanes (10 mL) then 1:1hexanes:Et₂O (2×10 mL) then purified on silica gel (250 mL) with 18:1DCM:MeOH yielding a hard yellow foam (1.78 g; 91%). LC (method B)t_(R)=13.5 min; ¹H NMR (200 MHz, CDCl₃) δ 8.70 (brs, 1H), 8.35 (m, 2H),7.47 (m, 3H), 7.16 (s, 1H), 6.48 (brs, 1H), 5.59 (brt, 1H), 4.19 (s,2H), 3.68 (m, 2H), 3.54 (m, 2H), 1.88 (s, 3H); ESIMS 347.9/349.9(100/32) [MH⁺].

EXAMPLE 2

Preparation of Not Commercially Available Amines 7

The syntheses of non-commercial amines 7 are shown in Scheme II. Benzylpiperidines were prepared by Horner-Wadsworth-Emmons reaction or fromN-Boc-4-methylenepiperidine by hydroboration and Suzuki cross-coupling.Phenyl ethers were synthesized from N-Boc-4-hydroxypiperidine and thephenols by Mitsunobu reaction. Alkylation of the nitrile 17.15 with theprotected nitrogen mustard 15 followed by Boc removal with HCl indioxane gave amine 7.15. The piperazines and homopiperazines wereprepared from the mono-Boc-protected derivatives by reductive aminationwith the appropriate aldehyde using NaBH(OAc)₃ as reducing agentfollowed by deprotection with TFA or HCl/MeOH.

4-Methylenepiperidine-1-carboxylic acid tert-butyl ester (13)Methyltriphenyl-phosphonium bromide (1.870 g; 5.23 mmol) was added inone portion to a suspension of KOtBu (0.586 g; 5.22 mmol) in anhydrousether (10 mL). After 30 min the yellow suspension was cooled to 0° C.,then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester(1.02 g; 5.12 mmol) was added. After 2.0 h water (10 mL) and EtOAc (10mL) were added; the organic portion was washed with water (2×10 mL) andsaturated NaCl (2×10 mL), dried (MgSO₄), filtered and concentrated to awhite solid. The material soluble in 12:1 hexanes:EtOAc was purified onsilica gel (60 mL) with this solvent system yielding a clear, colorlessliquid (685 mg; 68%). ¹H NMR (200 MHz, CDCl₃) δ 4.74 (t, J =1.0 Hz, 2H),3.42 (m, 4H), 2.18 (m, 4H), 1.47 (s, 9H).

4-(2-Chlorobenzyl)-piperidine-1-carboxylic acid tert-butyl ester (14.10)This compound was synthesized in a manner analogous to 14.12 from1-chloro-2-iodobenzene (264 mg; 1.11 mmol) giving a clear, colorless oil(262 mg; 76%) after silica gel chromatography (40 mL, eluting with 10:1hexanes:EtOAc). LC (method A) t_(R)=12.09 min; R_(f)=0.29 (SiO₂/8:1hexanes:EtOAc); ¹H NMR (200 MHz, CDCl₃) δ 7.35 (m, 1H), 7.16 (m, 3H),4.08 (m, 2H), 2.8-2.5 (m, 4H), 2.0-1.4(m, 3H), 1.45 (s, 9H), 1.23 (m,2H); ESIMS 294.9/296.9 (100/34) [MH⁺−C₄H₉+CH₃CN], 253.9/255.9 (40/12)[MH³⁰ −C₄H₉].

4-(3-Chlorobenzyl)-piperidine-1-carboxylic acid tert-butyl ester (14.11)This compound was synthesized in a manner analogous to 14.12 from1-bromo-3-chlorobenzene (223 mg; 1.16 mmol) giving a clear, pale yellowoil (204 mg; 57%) after silica gel chromatography (40 mL, eluting with9:1 hexanes:EtOAc). LC (method A) t_(R)=12.04 min; R_(f)=0.27 (SiO₂/9:1hexanes:EtOAc); ¹H NMR (200 MHz, CDCl₃) δ 7.3-7.1 (m, 3H), 7.00 (m, 1H),4.08 (m, 2H), 2.63 (m, 2H), 2.51 (m, 2H), 2.0-1.4 (m, 3H), 1.45 (s, 9H),1.16 (m, 2H); ESIMS 294.9/296.9 (100/34) [MH⁺−C₄H₉+CH₃CN], 253.9/255.9(32/10) [MH⁺−C₄H₉].

4-(4-Chlorobenzyl)-piperidine-1-carboxylic acid tert-butyl ester (14.12)A solution of alkene 13 (195 mg; 0.988 mmol) and 9-BBN (1.5 M in THF;2.0 mL; 1.0 mmol) was immersed in an oil bath at rt, heated to refluxand kept at reflux for 1.0 h then cooled to rt. This solution was addedto a suspension of 1-bromo-4-chlorobenzene (172 mg; 0.898 mmol), K₂CO₃(163 mg; 1.18 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (37 mg; 0.045 mmol) in water(0.20 mL) and DMF (2.0 mL). The reaction was degassed (reduced pressurethen nitrogen for three cycles) then heated at 60° C. for 3.0 h. Water(6 mL) and 1 M NaOH (6 mL) were added to the cooled solution and thiswas then extracted with EtOAc (15 mL). The organic portion was washedwith 1 M NaOH (4 mL), water (2×2 mL) and saturated NaCl (2×4 mL), thendried (MgSO₄). filtered and concentrated to a brown oil. Pure productwas obtained as a clear, colorless oil after chromatography on silicagel (40 mL), eluting with 8:1 hexanes:EtOAc (161 mg; 58%). LC (method A)t_(R)=12.10 min; R_(f)=0.30 (SiO₂/8:1 hexanes:EtOAc); ¹H NMR (200 MHz,CDCl₃) δ 7.24 (m, 2H), 7.06 (m, 2H), 4.07 (m, 2H), 2.63 (m, 2H), 2.50(m, 2H), 2.0-1.4 (m, 3H), 1.45 (s, 9H), 1.15 (m, 2H); ESIMS 309.8/311.8(1/0.4) [MH⁺], 294.9/296.9 (100/34) [MH⁺−C₄H₉+CH₃CN], 253.9/255.9(32/10) [MH⁺−C₄H₉], 210.0/212.0 (7/3) [MH⁺−C₄H₉−CO₂].

4-(2-Chlorobenzyl)-piperidine (7.10) Trifluoroacetic acid (1 mL) wasadded to carbamate 14.10 (256 mg; 0.826 mmol). After 0.5 h the reactionwas concentrated on a rotary evaporator. Ether (8 mL) was added and thesolution was washed with 5 M NaOH (2×3 mL) and water (3 mL). The productwas extracted into 1 M HCl (3×2 mL). After basification of the acidicportion with 5 M NaOH (4 mL), the product was extracted with DCM (3×2mL). The organic portion was dried (MgSO₄), filtered and concentratedaffording a clear, pale yellow liquid (137 mg; 79%). LC (method B)t_(R)=9.48 min; ¹H NMR (200 MHz, CDCl₃) δ 7.34 (m, 1H), 7.2-7.0 (m, 3H),3.05 (m, 2H), 2.66 (m, 2H), 2.54 (m, 2H), 1.9-1.5 (m, 3H), 1.21 (m, 2H);ESIMS 210.0/212.0 (100/35) [MH⁺].

4-(3-Chlorobenzyl)-piperidine (7.11) This compound was synthesized in amanner analogous to 7.10 from carbamate 14.11 (200 mg; 0.646 mmol)giving a clear, pale yellow viscous liquid which solidified uponstanding to a waxy solid (111 mg; 82%). LC (method B) t_(R)=9.84 min; ¹HNMR (200 MHz, CDCl₃) δ 7.3-7.1 (m, 3H), 7.01 (m, 1H), 3.05 (m, 2H),2.7-2.4 (m, 4H), 1.8-1.5 (m, 3H), 1.14 (m, 2H); ESIMS 210.0/212.0(100/35) [MH⁺].

4-(4-Chlorobenzyl)-piperidinium trifluoroacetate (7.12): Trifluoroaceticacid (1 mL) was added to carbamate 14.12 (153 mg; 0.494 mmol). After 0.8h the reaction was concentrated on a rotary evaporator. Ether (8 mL) wasadded and the resulting solid was triturated with ether, collected byfiltration and washed with ether leaving a white solid (143 mg; 89%). LC(method B) t_(R)=10.79 min; ¹H NMR (200 MHz, CDCl₃) δ 9.57 (brs, 1H),9.09 (brs, 1H), 7.27 (m, 2H), 7.06 (m, 2H), 3.38 (m, 2H), 2.82 (m, 2H),2.57 (m, 2H), 1.9-1.4 (m, 5H); ESIMS 210.0/212.0 (100/33) [MH⁺].

1-Benzyl-4-(4-methoxybenzylidene)-piperidine (12.8): A solution of1-benzylpiperidin-4-one (11) (2.310 g; 12.2 mmol) and(4-methoxybenzyl)-phosphonic acid diethyl ester (3.100 g; 12.0 mmol) inDME (20 mL) was added to NaH (0.51 g; 21 mmol). The flask was immersedin a rt oil bath, heated to reflux and kept at this temperature for 1.6h. The reaction was cooled, poured into water (200 mL) and extractedwith EtOAc (4×60 mL). The organic portion was washed with saturated NaCl(4×25 mL), dried (MgSO₄), filtered and concentrated to an oil. Theproduct was partially purified on silica gel (320 mL) with 25:1 DCM:MeOHgiving an oil (0.5 g). This oil was dissolved in 1 M HCl (10 mL) and theproduct was extracted into DCM (5×3 mL). The organic portion was washedwith saturated NaHCO₃, dried (MgSO₄), filtered and concentrated to anorange-brown liquid (0.46 g). This material was combined with crudematerial (2.41 g, unchromatographed) similarly prepared from ketone(1.535 g; 8.1 mmol), phosphonate (2.071 g; 8.02 mmol) and NaH (0.22 g;8.8 mmol). The combined crude material was purified on silica gel (250mL) with 2:1 hexanes:EtOAc giving a pale yellow solid (230 mg; 4%). mp71.5-72.0° C. ¹H NMR (200 MHz, CDCl₃) δ 7.4-7.2 (m, 5H), 7.12 (m, 2H),6.84 (m, 2H), 6.21 (m, 1H), 3.80 (s, 3H), 3.52 (s, 2H), 2.62.3 (m, 8H).

4-(4-Methoxybenzyl)-piperidine (7.8) Palladium hydroxide (27 mg) wasadded to a solution of N-benzyl alkene 10 (204 mg; 0.695 mmol) inmethanol (9 mL). The suspension was degassed then left under 1 atmhydrogen for 45 h. After filtration through a short pad of diatomaceousearth, the solution was concentrated in vacuo to a waxy solid (135 mg;95% crude yield). LC (method “polar_short”) t_(R)=3.01 min; ESIMS 206.0([M+H]⁺).

4-(3-Chlorophenoxy)-piperidine-1-carboxylic acid tert-butyl ester (10.5)A solution of DIAD (11.4 mL; 55.0 mmol) in THF (15 mL) was addeddropwise over 35 min to an ice-cold solution of4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (9) (10.06 g;50.0 mmol), 3-chlorophenol (5.1 mL; 50.4 mmol) and triphenylphosphine(14.44 g; 55.1 mmol) in THF (40 mL). After 2.9 days at room temperaturethe solvent was removed on a rotary evaporator leaving a viscous liquid;hexanes was added then evaporated leaving a solid. Ether (25 mL),followed by hexanes (100 mL), was added and the solid was filtered andwashed with hexanes. The filtrate was concentrated on a rotaryevaporator leaving a golden, viscous liquid (19.6 g). The crude productwas used as is. LC (method A) t_(R)=11.2 min; ESIMS 311.9/313.8 (25/10)[MH⁺], 296.9/298.8 (100/34) [MH⁺−C₄H₉+CH₃CN], 255.9/257.8 (94/32)[MH⁺−C₄H₉], 212.0/214.0 (13/5) [MH⁺−C₄H₉−CO₂].

4-(2-Chlorophenoxy)-piperidine-1-carboxylic acid tert-butyl ester (10.6)This compound was prepared from 4-hydroxypiperidine-1-carboxylic acidtert-butyl ester (9) (3.505 g; 17.4 mmol), 2-chloro-phenol (3.375 g;26.3 mmol), triphenylphosphine (6.002 g; 22.9 mmol) and DIAD (4.30 mL;21.8 mmol) in a manner analogous to 10.5. After 8 days, EtOAc (200 mL)was added to the crude reaction mixture and the solution washed with 50%saturated NaHCO₃ (50 mL), saturated NaHCO₃ (2×25 mL) and saturated NaCl(2×25 mL) then dried (MgSO₄), filtered and concentrated to a viscousliquid. Ether (50 mL) and hexanes (50 mL) were added and this wasallowed to stand overnight; whereupon the precipitate was removed byfiltration and the filtrate partially concentrated. More materialprecipitated, which was also removed by filtration, and the filtrate wasconcentrated to an oil. The product was partially purified on basicalumina (160 mL), eluting with 8:1 hexanes:EtOAc, giving a clear,colorless viscous liquid (5.12 g; 94% crude yield). LC (method A)t_(R)=11.50 min; ESIMS 312.1/314.1 (1/0.3) [MH⁺], 296.9/298.9 (100/34)[MH⁺−C₄H₉+CH₃CN], 255.9/257.8 (41/12) [MH⁺−C₄H₉], 212.0/214.0(4/1)[MH⁺−C₄H₉−CO₂].

Compounds 10.2-10.4 were prepared in an analogous manner.

4-(3-Chlorophenoxy)-piperidinium chloride (7.5): Trifluoroacetic acid(40 mL) was added to crude carbamate 10.5 (18.6 g; 59.7 mmol) cooled inan ice-water bath. After 1 min the reaction was stirred at rt for 15min, then concentrated on a rotary evaporator. Ether (200 mL) was addedand this washed with 3 M NaOH (3×50 mL) and water (50 mL). The productwas extracted into 1 M HCl (3×50 mL) and the aq phase was basified with3 M NaOH (60 mL). The free base was extracted into DCM (1×50 mL then2×25 mL), dried (MgSO₄), filtered and concentrated to an oil. Thehydrochloride salt was precipitated from a methanolic (6 mL) solution ofthe free base by the dropwise addition of HCl in ether (200 mL ofHCl-saturated ether plus 150 mL of ether). The salt was collected byfiltration and washed with ether (100 mL) giving an off-white solid(7.97 g; 68% from 4-hydroxypiperidine-1-carboxylic acid tert-butylester). LC (method B) t_(R)=8.2 min; ¹H NMR (200 MHz, DMSO-d₆) δ 8.94(brs, 2H), 7.33 (m, 1H), 7.12 (m, 1H), 7.00 (m, 2H), 4.70 (m, 1H), 3.20(m, 2H), 3.08 (m, 2H), 2.08 (m, 2H), 1.85 (m, 2H); ESIMS (free base)212.0/213.9 (100/35) [MH⁺].

4-(2-Chlorophenoxy)-piperidine (7.6): Trifluoroacetic acid (4 mL) wasadded to crude carbamate 10.6 (1.030 g). After 20 min at rt most of thevolatiles were removed in vacuo and 1 M HCl (10 mL) was added, whereuponan oil separated. This was washed with DCM (3×3 mL). The aqueous portionwas basified to pH>12 with 5 M NaOH, extracted with DCM (3×4 mL), dried(MgSO₄), filtered and concentrated to an oil (10 mg). The initial DCMwashing was dried (MgSO₄), filtered and concentrated to a pale yellowoil (1.26 g), whose ¹H NMR was consistent with being the piperidiniumtrifluoroacetate. This material, plus the initial collected free base(10 mg) was dissolved in ether (30 mL) and washed with 5 M NaOH (10 mL),1 M NaOH (2×10 mL), water (10 mL) and saturated NaCl (2×10 mL), thendried (MgSO₄) and filtered. HCl-saturated ether (35 mL) was added andthe turbid solution was extracted with 1 M HCl (3×10 mL). The acidicportion was basified with 5 M NaOH, extracted with DCM (3×8 mL) and theorganic portion dried (MgSO₄), filtered and concentrated to a paleyellow oil (457 mg; 62% from 4-hydroxypiperidine-1-carboxylic acidtert-butyl ester). LC (method B) t_(R)=8.2 min; ¹H NMR (200 MHz, CDCl₃)δ 7.37 (dd, J=1.6, 8.0 Hz, 1H), 7.19 (ddd, J=1.5, 7.3, 8.6 Hz, 1H),7.0-6.8 (m, 2H), 4.42 (tt, J=3.9, 3.9 Hz, 1H), 3.18 (ddd, J=4.0, 6.3,12.0 Hz, 2H), 2.73 (ddd, J=3.7, 8.6, 12.3 Hz, 2H), 2.00 (m, 2H), 1.77(m, 2H); ESIMS (free base) 212.0/213.9 (100/37) [MH⁺].

Compounds 7.2-7.4 were prepared in an analogous manner.

General Procedures for the Reductive Amination of Boc-ProtectedPiperazines and Homopiperazine with Aldehydes and Deprotection with TFA

4-(3-Chlorobenzyl)-piperazine-1-carboxylic acid tert-butyl ester(20.24): To a solution of piperazine-1-carboxylic acid tert-butyl ester(4.00 g, 21.5 mmol) in dry dichloroethane (70 mL) are added3-chlorobenzaldehyde (2.49 mL, 3.08 g, 21.9 mmol), HOAc (2.58 mL, 2.71g, 45.1 mmol) and NaBH(OAc)₃ (5.46 g, 25.8 mmol) at ambient temperature.After stirring at ambient temperature for 3d, 2N NaOH (40 mL) is added,the layers are separated, and the aqueous layer is extracted with CH₂Cl₂(4×50 mL). The combined organic extracts are washed with water (3×50 mL)and brine (80 mL) and dried over MgSO₄. The crude material is purifiedby chromatography on silica gel, eluting with hexane:EtOAc mixtures,yielding 5.83 g (18.8 mmol, 87%) of the title compound as yellow oil. MS(ES): m/z 311.0/313.0 (50/18) [MH⁺]. t_(R) (method A)=5.0 min.

1-(3-Chlorobenzyl)-piperazine (7.24): To4-(3-chlorobenzyl)-piperazine-1-carboxylic acid tert-butyl ester (20.24)(8.82 g, 28.4 mmol) is added TFA (45 mL) at ambient temperature over 5min. After 1 h 50 min, TFA is evaporated, the residue is dissolved in 2NHCl (45 mL) and extracted with ether (2×45 mL). The aqueous layer isbasified to pH 13 with 2N NaOH (60 mL) and extracted with CH₂Cl₂ (6×90mL). The combined organic extracts are washed with brine (75 mL) anddried over MgSO₄. The crude material obtained after filtration andconcentration (5.44 g, 25.8 mmol, 91%) is used without furtherpurification. MS (ES): m/z 211.0/213.0 (100/35) [MH⁺]. t_(R) (methodB)=5.1 min.

4-(3-Trifluoromethylbenzyl)-[1,4]diazepane-1-carboxylic acid tert-butylester (20.40): The procedure for the corresponding 3-chlorobenzylpiperazine was used. The title compound was obtained as yellow oil (87%yield). MS (ES): m/z 359.0 (81) [MH⁺]. t_(R) (method A)=4.9 min.

1-(3-Trifluoromethylbenzyl)-[1,4]diazepane (7.40): The procedure for thecorresponding 3-chlorobenzyl piperazine was used. The title compound wasobtained as yellow oil (93% yield) and is used without furtherpurification. MS (ES): m/z 259.1 (100) [MH⁺]. t_(R) (method A)=3.4 min.

4-Benzyl-cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester(20.16): The procedure for the corresponding 3-chlorobenzyl piperazinewas used. The title compound was obtained as yellow oil (34% yield)after chromatography on silica gel. ¹H NMR (200 MHz, CDCl₃) δ 7.40-7.18(m, 5H), 3.90-3.80 (m, 2H), 3.81 (s, 2H), 2.72-2.50 (m, 4H), 1.45 (s,9H), 1.04 (d, J=6.0 Hz, 6H).

General Procedure for the removal of Boc groups with HCl/MeOH: Acetylchloride (1.5 ML, 21 mmol) is added dropwise into dry methanol (8 mL) atambient temperature. After 10 min, this solution is added to a solutionof the Boc-protected amine (0.9 mmol), and the reaction is stirred atambient temperature. Upon complete consumption of starting material asjudged by TLC, the solvents are evaporated. The residue (aminehydrochloride) is used directly for the amide formation.

1-Benzyl-cis-2,6-dimethylpiperazine dihydrochloride (7.16): Followingthe general procedure, the title compound was obtained from4-benzyl-cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl esteras beige solid (quant.). MS (ES, free base): m/z 205.1 (100) [MH⁺].t_(R) (method B, free base)=5.8 min.

Bis-(2-chloroethyl)-carbamic acid tert-butyl ester (16): To a suspensionof bis(2-chloroethyl)amine hydrochloride (10.05 g, 56.3 mmol) and Boc₂O(13.6 g, 62.3 mmol) in CH₂Cl₂ (70 mL), cooled by ice/water, was addedtriethylamine (9.5 mL, 68.2 mmol). After 45 min, the cooling bath wasremoved, and the reaction mixture was stirred at ambient temperatureovernight. Water (50 mL) was added, and the mixture was extracted withether:hexanes 1:1 (3×100 mL). The combined organic layers were washedwith water (2×) and brine, dried over MgSO₄ and concentrated to give apale yellow liquid, which was a 1:1 mixture of 16 and Boc₂O. Thereaction was therefore repeated with this material twice, first with5.89 g (33.0 mmol) of 15 and 4.8 mL of NEt₃ (34 mmol) and then with 2.5g (14 mmol) of 15 and 2.3 mL of NEt₃ (17 mmol). This gave 14.887 g (61.5mmol, 99%) of the known amine 16 as pale yellow liquid, pure by ¹H NMRand TLC. ¹H NMR (200 MHz, CDCl₃): δ=1.47 (s, 9H), 3.55-3.70 (brm, 8H).

4-(2-Chlorophenyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester(18.15): To a suspension of NaH (60% oil suspension, 7.37 g, 184.4 mmol)in DMF (110 mL), cooled by ice/water, was added a solution of thenitrile 17.15 (9.782 g, 64.52 mmol) in DMF (20 mL) over 20 min. Hydrogenevolved, and the reaction mixture turned yellow. After 30 min, asolution of the chloroamine 16 (14.88 g, 61.45 mmol) in DMF (15 mL) wasadded. After 15 min the cooling bath was removed, and the reactionmixture was heated to 75° C. (bath temperature) for 5.5 h. TLC indicatedthe complete consumption of both 16 and 17.15. The DMF was evaporated.Upon addition of water and ether (200 mL each) a solid separated, whichwas filtered off, washed thoroughly with ether and EtOAc, and dried,yielding 8.018 g (24.99 mmol, 41%) of 18.15. The layers of the combinedfiltrate and washings were separated, and the aqueous layer wasextracted with more ether (2×150 mL). The combined organic layers werewashed with 5% HOAc, water, 1N NaOH, water, and brine and dried overMgSO₄. This solution was filtered through a pad of silica gel. Uponconcentration a solid precipitated, which was filtered off, washed withether and hexanes and dried, yielding 6.138 g (19.13 mmol, 31%) of18.15. The mother liquor was concentrated and the residue purified bycolumn chromatography on silica gel, yielding 2.885 g (8.99 mmol, 15%)of 18.15. The total yield was 17.04 g (53.12 mmol, 86%), mp 165-166° C.¹H NMR (200 MHz, CDCl₃): δ=1.48 (s, 9H), 2.00 (brdt, J=4.2, 13.0 Hz,2H), 2.43-2.53 (m, 2H), 3.28 (brt, J=12.8 Hz, 2H), 4.28 (brd, J=13.2 Hz,2H), 7.28-7.50 (m, 4H). C₁₇H₂₁ClN₂O₂ (320.82): calcd. C, 63.65, H, 6.60,Cl, 11.05, N, 8.73; found C, 63.82, H, 6.61, Cl, 10.90, N, 8.72.

4-(2-Chlorophenyl)-piperidine-4-carbonitrile hydrochloride (7.15): Asolution of HCl in dioxane (4M, 200 mL, 800 mmol) was added to theBoc-protected amine 18.15 (18.4 g, 57.4 mmol). After 1.5 h the solventwas evaporated and the residue dried in vacuo, giving 14.8 g (57.4 mmol,100%) of 7.15, colorless solid, mp 241-243° C. (decomp.). ¹H NMR (200MHz, CDCl₃): δ=2.5-2.8 (brm, 4H), 3.4-3.6 (brm, 2H), 3.6-3.8 (brm, 2H),7.33-7.39 (m, 3H), 7.48-7.53 (m, 1H), 10.01 (brs, 2H). C₁₂H₁₄Cl₂N₂(257.16): calcd. C, 56.05, H, 5.49, Cl, 27.57, N, 10.89; found C, 55.67,H, 5.48, Cl, 27.86, N, 10.61.

EXAMPLE 3

Synthesis of Hydroxy-Piperidines for Displacement Reactions.

Known amines 7.57, 7.66, 7.103 and 7.126 were prepared as described inJ. Med. Chem. (1999), 42(12): 2087-2104 and in U.S. Pat. No. 5,889,026.

EXAMPLE 4

Preparation of A_(2B) Antagonists 8

The chloroacetamide 6 was reacted with amines 7 (free bases or HCl orTFA salts) to give the target compounds 8 (Scheme III); see Scheme IVfor library-format synthesis and characterization data of 8.47-8.128.Selected compounds were converted to their HCl salts.

TABLE 1 A_(2B) antagonists 8.1-8.46 Comp. # Structure MW 8.1

488.59 8.2

523.04 8.3

518.62 8.4

488.59 8.5

523.04 8.6

523.04 8.7

472.60 8.8

516.65 8.9

504.61 8.10

521.07 8.11

521.07 8.12

521.07 8.13

502.62 8.14

497.61 8.15

532.05 8.16

515.66 8.17

473.58 8.18

487.61 8.19

517.64 8.20

517.64 8.21

517.64 8.22

522.05 8.23

522.05 8.24

522.05 8.25

505.60 8.26

505.60 8.27

555.61 8.28

488.60 8.29

488.60 8.30

488.60 8.31

493.66 8.32

501.64 8.33

487.61 8.34

515.66 8.35

501.64 8.36

519.63 8.37

519.63 8.38

519.63 8.39

569.64 8.40

569.64 8.41

569.64 8.42

502.62 8.43

536.08 8.44

502.62 8.45

516.65 8.46

523.03

Preparation of the A_(2B) antagonists 8 (when no details are given, thenthe preparation was carried analogously to 8.6):

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(3-phenoxypiperidin-1-yl)-acetamide(8.1): MS (ES) 489 (M⁺); t_(R) (method B)=14.1 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorophenoxy)-piperidin-1-yl]-acetamide(8.2): MS (ES) 522.9/524.9 (92/32) [MH⁺], 480.9/482.8 (88/29)[MH⁺−CH₂═CO]; t_(R) (method B)=14.3 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-methoxyphenoxy)-piperidin-1-yl]-acetamide(8.3): MS (ES) 519 (M⁺); t_(R) (method B)=12.6 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-phenoxypiperidin-1-yl)-acetamide(8.4): MS (ES) 489 (M⁺); t_(R) (method B)=12.8 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorophenoxy)-piperidin-1-yl]-acetamide(8.5): This compound was prepared from chloroacetamide 6 (37 mg; 0.11mmol), piperidinium salt 7.5 (35 mg; 0.14 mmol), DIPEA (47 μL; 0.27mmol) and sodium iodide (16 mg; 0.11 mmol) in a manner analogous to 8.6yielding a hard white foam after silica gel chromatography (47.8 mg;86%). LC (method B) t_(R)=13.6 min; ¹H NMR (200 MHz, CDCl₃) δ 9.49 (s,1H), 8.37 (m, 2H), 7.48 (m, 3H), 7.27-7.15 (m, 2H), 6.93 (m, 2H), 6.81(m, 1H), 6.50 (brs, 1H), 5.39 (brt, J=5.0 Hz, 1H), 4.41 (m, 1H), 3.68(m, 2H), 3.53 (m, 2H, 3.19 (s, 2H), 2.86 (m, 2H), 2.56 (m, 2H),2.20-1.91 (m, 4H). 1.86 (s, 3H). ESIMS 523.0/525.0 (100/42) [MH⁺], 262(60), 198 (73).

Large scale reaction: Sodium iodide (2.45 g; 16.3 mmol) was added to asuspension of chloroacetamide 6 (5.67 g; 16.3 mmol), piperidiniumchloride 7.5 (4.85 g; 19.5 mmol) and DIPEA (7.0 mL; 40.2 mmol) in 3:1acetonitrile:THF (480 mL). After 19.5 h the reaction was concentrated ona rotary evaporator. EtOAc (250 mL) was added and the suspension waswashed with 50% saturated NaHCO₃ (1×50 mL), water (2×25 mL) andsaturated NaCl (2×35 mL). The orange-brown solution was dried overMgSO₄; charcoal (0.86 g) was added and this was filtered thenconcentrated leaving a light orange foam. The crude material waspurified on silica gel (850 mL) with 12-9:1 EtOAc:i-PrOH. Product wasobtained as a pale yellow/off-white hard foam (7.82 g; 92%).

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorophenoxy)-piperidin-1-yl]-acetamidedihydrochloride (8.5-2HCl): Hydrogen chloride in dioxane (4 M; 6.5 mL;26 mmol) was added to a solution of free base 8.5 (3.38 g; 6.46 mmol) inmethanol (34 mL). The slightly turbid solution was filtered through aplug of glass wool and the glassware rinsed with methanol (2×5 mL).Anhydrous ether was carefully added until a persistent precipitate justformed (56 mL). After 1 h at room temperature the flask was put into arefrigerator overnight. The white precipitate was collected on a Büchnerfunnel and rinsed with 4:1 ether:methanol (30 mL), 9:1 ether:methanol(30 mL) and ether (50 mL). Product was obtained as a white solid (2.88g; 75%), mp. 195° C. (decomp.). ESIMS 522.9/524.9 (80/28) [MH⁺], 262.0(50), 198.0 (100). ¹H NMR (D₂O) δ 8.14 (m, 2H), 7.83-7.62 (m, 4H), 7.40(m, 1H), 7.22-7.01 (m, 3H), 4.87 (m, 1H), 4.43 (s, 2H), 3.82-3.46 (m,8H), 2.31 (m, 4H), 1.94 (s, 3H). UV (MeOH): λ_(max)/nm (log ε)=237(4.72), 205 (4.78).

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorophenoxy)-piperidin-1-yl]-acetamide(8.6): Sodium iodide (19 mg; 0.13 mmol) was added to a solution ofchloroacetamide 6 (40 mg; 0.12 mmol), piperidine 7.6 (31 mg; 0.15 mmol)and DIPEA (30 μL; 0.17 mmol) in 3:1 acetonitrile:THF (2 mL). After 22 hthe reaction was filtered through a short plug of silica gel with THF asa wash. The solution was concentrated in vacuo then purified on silicagel (20 mL) with 10:1 EtOAc:i-PrOH yielding a hard white foam (59.2 mg;98%). LC (method B) t_(R)=12.9 min; ¹H NMR (200 MHz, CDCl₃) δ 9.51 (s,1H), 8.37 (m, 2H), 7.47 (m, 3H), 7.38 (m, 1H), 7.31-7.14 (m, 2H),7.02-6.86 (m, 2H), 6.72 (brs, 1H), 5.69 (brt, J=5.6 Hz, 1H), 4.48 (m,1H), 3.67 (m, 2H), 3.53 (m, 2H), 3.19 (s, 2H), 2.90 (m, 2H), 2.56 (m,2H), 2.20-2.00 (m, 4H), 1.86 (s, 3H). ESIMS 523.0/525.0 (100/42) [MH⁺],262 (58), 198 (75).

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-phenylpiperidin-1-yl)acetamide(8.7): MS (ES) 473 (M⁺); t_(R) (method B)=4.1 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-methoxybenzyl)-piperidin-1-yl]-acetamide(8.8): A solution of chloroacetamide 6 (41 mg; 0.118 mmol), piperidine7.8 (27 mg; 0.132 mmol) and DIPEA (30 μL; 0.172 mmol) in 2.5 mL of 3:2acetonitrile:THF was reacted at rt for 8 days; whereupon the reactionwas concentrated on a rotary evaporator then purified on silica gel (20mL) with 12:1 EtOAc:i-PrOH yielding a glassy material. A solution of theproduct in DCM plus hexanes was evaporated leaving a white solid (23 mg;38%). LC (method B) t_(R)=12.8 min; ¹H NMR (200 MHz, CDCl₃) δ 9.53 (brs,1H), 8.37 (m, 2H), 7.48 (m, 3H), 7.22 (s, 1H), 7.08 (m, 2H), 6.84 (m,3H), 6.62 (brs, 1H), 5.50 (brt, J=5.5 Hz, 1H), 3.79 (s, 3H), 3.68 (m,2H), 3.53 (m, 2H), 3.10 (s, 2H), 2.88 (m, 2H), 2.54 (m, 2H), 2.20 (m,2H), 1.85 (s, 3H), 1.80-1.20 (m, 5H); ESIMS 517.0 (28) [MH⁺], 259.1(100).

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-fluorobenzyl)-piperidin-1-yl]-acetamide(8.9): This compound was prepared from chloroacetamide 6 (77 mg; 0.221mmol) and 4-(4-fluorobenzyl)-piperidine (7.9) (47 mg; 0.24 mmol) in amanner analogous to 8.8 yielding a white crystalline solid (80.5 mg;72%) after silica gel chromatography (12-8:1 EtOAc:i-PrOH). LC (methodB) t_(R)=13.1 min; ¹H NMR (200 MHz, CDCl₃) δ 9.51 (brs, 1H), 8.37 (m,2H), 7.48 (m, 3H), 7.22 (s, 1H), 7.11 (m, 2H), 6.98 (m, 2H), 6.58 (brs,1H), 5.45 (brt, J=5.4 Hz, 1H), 3.68 (m, 2H), 3.53 (m, 2H), 3.11 (s, 2H),2.89 (m, 2H), 2.57 (m, 2H), 2.20 (m, 2H), 1.86 (s, 3H), 1.80-1.30 (m,5H); ESIMS 505.0 (42) [MH⁺], 253.1 (100).

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorobenzyl)-piperidin-1-yl]-acetamide(8.10): This compound was prepared from chloroacetamide 6 (40 mg; 0.12mmol) and piperidine 7.10 (29 mg; 0.14 mmol) in a manner analogous to8.6, yielding a hard white foam after silica gel chromatography (33.9mg; 57%). LC (method B) t_(R)=12.5 min; ¹H NMR (200 MHz, CDCl₃) δ 9.52(s, 1H), 8.38 (m, 2H), 7.49 (m, 3H), 7.40-7.08 (m, 5H), 6.83 (brs, 1H),5.83 (brt, J=5.6 Hz, 1H), 3.66 (m, 2H), 3.52 (m, 2H), 3.11 (s, 2H), 2.88(m, 2H), 2.73 (m, 2H), 2.20 (m, 2H), 1.85 (s, 3H), 1.80-1.35 (m, 5H).ESIMS 521.0/523.0 (41/18) [MH⁺], 479.0/481.0 (50/20) [MH⁺−CH₂═CO], 261(100).

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorobenzyl)-piperidin-1-yl]-acetamide(8.11): This compound was prepared from chloroacetamide 6 (40 mg; 0.12mmol) and piperidine 7.11 (29 mg; 0.14 mmol) in a manner analogous to8.6 yielding a white solid after silica gel chromatography (54.0 mg;90%). LC (method B) t_(R)=12.5 min; ¹H NMR (200 MHz, CDCl₃) δ 9.49 (s,1H), 8.37 (m, 2H), 7.48 (m, 3H), 7.26-7.11 (m, 4H), 7.04 (m, 1H), 6.56(brs, 1H), 5.45 (brt, J=5.5 Hz, 1H), 3.68 (m, 2H), 3.52 (m, 2H), 3.11(s, 2H), 2.89 (m, 2H), 2.58 (m, 2H), 2.21 (m, 2H), 1.86 (s, 3H),1.79-1.34 (m, 5H). ¹³C NMR (50.3 MHz, CDCl₃) δ 171.0, 170.7, 164.5,163.6, 156.0, 142.4, 137.7, 134.0, 130.5, 129.5, 129.1, 128.3, 127.9,127.3, 126.1, 89.8, 62.6, 54.2, 42.6, 40.9, 37.1, 32.1, 23.1. ESIMS521.0/523.0 (42/18) [MH⁺], 479.0/481.0 (55/22) [MH⁺−CH₂═CO], 261 (100).

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorobenzyl)-piperidin-1-yl]-acetamide(8.12): This compound was prepared from chloroacetamide 6 (40 mg; 0.12mmol), piperidinium salt 7.12 (45 mg; 0.14 mmol), DIPEA (50 μL; 0.29mmol) and sodium iodide (19 mg; 0.13 mmol) in a manner analogous to 8.6yielding a white crystalline solid after silica gel chromatography (45.8mg; 76%). LC (method B) t_(R)=12.6 min; ¹H NMR (400 MHz, CDCl₃) δ 9.49(s, 1H), 8.36 (m, 2H), 7.48 (m, 3H), 7.26 (m, 2H), 7.22 (s, 1H), 7.09(m, 2H), 6.56 (brs, 1H), 5.41 (brs, 1H), 3.68 (m, 2H), 3.52 (m, 2H),3.10 (s, 2H), 2.88 (m, 2H), 2.57 (m, 2H), 2.19 (m, 2H), 1.85 (s, 3H),1.66 (m, 2H), 1.54 (m, 1H), 1.44 (m, 2H). ESIMS 521.0/523.0 (55/22)[MH⁺], 479.0/481.0 (67/23) [MH⁺−CH₂═CO], 261 (100).

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-benzyl-4-hydroxy-piperidin-1-yl)-acetamide(8.13): MS (ES) 503 (M⁺); t_(R) (method B)=3.8 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimdin-4-yl]-2-(4-cyano-4-phenyl-piperidin-1-yl)-acetamide(8.14): MS (ES) 498 (M⁺); t_(R) (method B)=5.8 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorophenyl)-4-cyanopiperidin-1-yl]-acetamide(8.15): MS (ES) 531.9/533.9 (100/39) [MH⁺]; t_(R) (method B)=6.1 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-benzyl-cis-3,5-dimethylpiperazin-1-yl)-acetamide(8.16): MS (ES) 516 (M⁺); t_(R) (method B)=11.5 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-phenylpiperazin-1-yl)-acetamide(8.17): MS (ES) 474 (M⁺); t_(R) (method B)=4.9 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-benzylpiperazin-1-yl)-acetamide(8.18): MS (ES) 488 (M⁺); t_(R) (method B)=3.7 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-methoxybenzyl)-piperazin-1-yl]-acetamide(8.19): MS (ES) 518 (M⁺); t_(R) (method B)=4.0 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-methoxybenzyl)-piperazin-1-yl]-acetamide(8.20): MS (ES) 518 (M⁺); t_(R) (method B)=11.4 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-methoxybenzyl)-piperazin-1-yl]-acetamide(8.21): MS (ES) 518 (M⁺); t_(R) (method B)=11.2 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorobenzyl)-piperazin-1-yl]-acetamide(8.22): MS (ES) 521.9/523.9 (100/38) [MH⁺], 397.9 (69) [MH⁺−3-ClPhCH₂];t_(R) (method B)=3.7 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorobenzyl)-piperazin-1-yl]-acetamide(8.23): MS (ES) 522.0/524.0 (12/4) [MH⁺], 397.9 (100) [MH⁺−3-ClPhCH₂];t_(R) (method B)=11.8 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorobenzyl)-piperazin-1-yl]-acetamide(8.24): MS (ES) 522.0/524.0 (14/5) [MH⁺], 398.0 (100) [MH⁺3-ClPhCH₂]; ¹HNMR (200 MHz, CDCl₃) δ 9.45 (s, 1H), 8.41-8.32 (m, 2H), 7.55-7.42 (m,3H), 7.36 (s, 1H), 7.27-7.18 (m, 4H), 6.46 (brs, 1H), 5.35 (brs, 1H),3.75-3.62 (m, 2H), 3.58-3.47 (m, 2H), 3.55 (s, 2H), 3.17 (s, 2H),2.71-2.52 (m, 8H), 1.86 (s, 3H); t_(R) (method B)=12.1 min; t_(R)(method A)=5.5 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorobenzyl)-piperazin-1-yl]-acetamidetrihydrochloride (8.24-3HCl): Prepared similarly to 8.40.3HCl andtriturated with acetone. Off-white solid, mp. 192-194° C. (decomp.). MS(ES) 522.0/524.0 (38/13) [MH⁺], 398.0 (100) [MH⁺−3-ClPhCH₂]. ¹H NMR (200MHz, D₂O) δ 8.14-8.02 (m, 2H), 7.83-7.43 (m, 8H), 4.44 (s, 2H),3.90-3.62 (m, 4H), 3.60-3.45 (m, 4H), 3.48 (s, 2H), 3.22 (brs, 4H), 1.88(s, 3H). UV (MeOH): λ_(max)/nm (log ε)=238 (4.63), 209 (4.59).

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-fluorobenzyl)-piperazine-1-yl]-acetamide(8.25): (20%) ¹H NMR (200 MHz, CDCl₃) δ 9.44 (s, 1H), 8.36 (m, 2H), 7.46(m, 3H), 7.21 (m, 2H), 7.11 (m, 3H), 6.95 (m, 1H), 6.60 (m, 1H), 5.55(m, 1H), 3.66 (m, 2H), 3.56 (m, 4H), 3.16 (s, 2H), 2.63 (m, 8H), 1.85(s, 3H). MS (ES) 506 (M⁺). t_(R) (method B)=9.5 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-fluorobenzyl)-piperazine-1-yl]-acetamide(8.26): (54%) ¹H NMR (200 MHz, CDCl₃) δ 9.44 (s, 1H), 8.33 (m, 2H), 7.48(m, 3H), 7.29-7.04 (m, 7H) 6.54 (m, 1H), 5.44 (m, 1H), 3.66 (m, 4H) 3.53(m, 2H), 3.15 (s, 2H), 2.65 (m, 8H) 1.86 (s, 3H). MS (ES) 506 (M⁺).t_(R) (method B)=9.2 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-trifluoromethyl-benzyl)-piperazine-1-yl]-acetamide(8.27): (28%) ¹H NMR (200 MHz, CDCl₃) δ 9.45 (s, 1H), 8.36 (m, 2H),7.62-7.48 (m, 7H), 7.22 (s, 1H), 6.52 (m, 1H), 5.44 (m, 1H), 3.68 (m,2H, 3.63 (s, 2H), 3.54 (m, 2H), 3.17 (s, 2H), 2.63 (m, 8H), 1.86 (s,1H). MS (ES) 556 (M⁺). t_(R) (method A)=10.9 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-pyridin-3-ylmethyl-piperazine-1-yl)-acetamide(8.28): (69%) ¹H NMR (200 MHz, CDCl₃) δ 9.42 (s, 1H), 8.56 (s, 1H) 8.50(d, 1H, J=4.0 Hz), 8.36 (m, 2H), 7.67 (d, 1H, J=8.0 Hz), 7.45 (m, 3H),7.29-7.20 (m, 2H), 6.59 (m, 1H), 5.54 (m, 1H), 3.66 (m, 2H), 3.57-3.49(m, 4H), 3.15 (s, 2H), 2.61 (m, 8H), 1.85 (s, 3H). MS (ES) 489 (M⁺).t_(R) (method B)=6.7 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-pyridin-2-ylmethyl-piperazine-1-yl)-acetamide(8.29): (54%) ¹H NMR (200 MHz, CDCl₃+CD₃OD) δ 8.52 (d, 1H, J=3.6 Hz)8.31 (m, 2H), 7.74 (ddd, 1H, J=7.4 Hz, 5.8 Hz, 1.5 Hz) 7.48 (m, 4H),7.24 (dd, 1H, J=6.6 Hz, 5.8 Hz), 7.16 (s, 1H), 3.74 (s, 2H), 3.64 (m,2H) 3.41 (m, 4H), 3.18 (s, 2H), 2.69 (m, 8H), 1.86 (s, 3H). MS (ES) 489(M⁺). t_(R) (method B)=7.4 min.

N-[6-(2-Acetlaminoethylamino)-2-phenylpyrimidin-4yl]-2-(4-pyridin-4-ylmethyl-piperazine-1-yl)-acetamide(8.30): (47%) ¹H NMR (200 MHz, CDCl₃) δ 9.43 (s, 1H), 8.55 (d, 2H, J=5.8Hz), 8.36 (m, 2H), 7.26 (m, 3H), 7.28 (d, 2H, J=6.0 Hz), 6.60 (m, 1H),5.56 (m, 1H) 3.67 (m, 2H), 3.58 (m, 4H) 3.17 (s, 2H), 2.63 (m, 8H) 1.86(s, 3H). MS (ES) 489 (M⁺). t_(R) (method B)=6.1 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-cyclohexylmethyl-piperazin-1-yl)-acetamide(8.31): MS (ES) 494 (M⁺); t_(R) (method B)=3.9 min. yl)-acetamide(8.32): MS (ES) 502 (M⁺); t_(R) (method B)=3.9 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-phenyl-[1,4]diazepan-1-yl)-acetamide(8.33): MS (ES) 489 (M⁺); t_(R) (method B)=4.6 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-phenethyl-[1,4]diazepan-1-yl)-acetamide(8.34): MS (ES) 516 (M⁺); t_(R) (method B)=3.9 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-benzyl-[1,4]diazepan-1-yl)-acetamide(8.35): MS (ES) 502 (M⁺); t_(R) (method B)=3.7 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4yl]-2-[4-(2-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide(8.36): (60%). ¹H NMR (200 MHz, CDCl₃) δ 9.69 (s, 1H) 8.42 (m, 2H), 7.53(m, 3H), 7.32 (m, 3H), 7.14 (m, 2H), 6.74 (m, 1H), 5.68 (m, 1H) 3.85 (s,2H), 3.74 (m, 2H), 3.60 (m, 2H), 3.38 (s, 2H), 2.91 (m, 8H), 1.93 (m,5H). MS (ES) 520 (M⁺). t_(R) (method B)=9.1 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4yl]-2-[4-(3-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide(8.37): (45%) ¹H NMR (200 MHz, CDCl₃) δ 9.63 (s, 1H), 8.36 (m, 2H), 7.48(m, 3H), 7.21 (m, 4H), 6.91 (m, 1H), 6.53 (m, 1H) 5.51 (m, 1H), 3.71 (m,4H), 3.53 (m, 2H), 3.31 (s, 2H), 2.80 (m, 8H), 1.86 (m, 5H). MS (ES) 520(M⁺). t_(R) (method A)=9.4 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4yl]-2-[4-(4-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide(8.38): (64%) ¹H NMR (200 MHz, CDCl₃) δ 9.64 (s, 1H), 8.36 (m, 2H), 7.48(m, 3H), 7.37-7.26 (m, 3H) 6.99 (dd, 2H, J=8.6 Hz, 8.8 Hz) 6.53 (m, 1H),5.39 (m, 1H), 3.67 (m, 4H), 3.54 (m, 2H), 3.31 (s, 2H) 2.83 (m, 8H),1.86 (5H). MS (ES) 520 (M⁺). t_(R) (method A)=9.4 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4yl]-2-[4-(2-trifluoromethylbenzyl)-[1,4]diazapan-1-yl]-acetamide(8.39): (54%) ¹H NMR (200 MHz, CDCl₃) δ 9.67 (s, 1H), 8.36 (m, 2H), 7.87(d, 1H, J=8.2 Hz) 7.62 (d, 1H, J=7.4 Hz) 7.48 (m, 4H), 7.26-7.22 (m,2H), 6.60 (m, 1H), 5.45 (m, 1H) 3.85 (s, 2H), 3.68 (m, 2H), 3.53 (m,2H), 3.49 (s, 2H), 2.81 (m, 8H), 1.85 (m, 5H). MS (ES) 570 (M⁺). t_(R)(method B)=10.9 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-trifluoromethylbenzyl)-[1,4]diazepan-1-yl]-acetamide(8.40): Sodium iodide (903 mg; 6.02 mmol) was added to a solution ofchloroacetamide 6 (2.088 g; 6.00 mmol),1-(3-trifluoromethylbenzyl)-[1,4]diazepane (7.40) (1.863 g; 7.21 mmol)and DIPEA (1.45 mL; 8.32 mmol) in 3:1 acetonitrile:THF (30 mL). After 21h the reaction was concentrated on a rotary evaporator. EtOAc (90 mL)was added and the suspension was washed with 50% saturated NaHCO₃ (25mL), water (3×25 mL) and saturated NaCl (2×25 mL). The solution wasdried (MgSO₄), filtered, concentrated to an oil then purified on silicagel (340 mL), eluting with 9:1 EtOAc:methanol. Pure product was obtainedas a hard white foam (3.10 g; 91%). LC (method B) t_(R)=12.6 min; ¹H NMR(200 MHz, CDCl₃) δ 9.64 (s, 1H), 8.36 (m, 2H), 7.7-7.3 (m, 7H), 7.22 (s,1H), 6.56 (brs, 1H), 5.42 (brt, J=5.8 Hz, 1H), 3.75 (s, 2H), 3.68 (m,2H), 3.54 (m, 2H), 3.32 (s, 2H), 3.0-2.7 (m, 8H), 1.93 (m, 2H), 1.65 (s,3H). ESIMS 570 (12) [MH⁺], 286 (100).

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-trifluoromethylbenzyl)-[1,4]diazepan-1-yl]-acetamidetrihydrochloride (8.40.3HCl): HCl-saturated methanol (10 mL) was addedto a solution (10 mL) of free base 8.40 (2.88 g; 5.06 mmol) in methanol(10 mL). The solution was filtered then concentrated in vacuo affordingproduct as an off-white hard foam (3.30 g; 96%), mp. 160° C. (decomp.).LC (method B) t_(R)=12.5 min; ¹H NMR (D₂O) δ 8.08 (m, 2H), 7.87 (m, 2H),7.79 (m, 1H), 7.70 (m, 2H), 7.61 (m, 2H), 4.55 (s, 2H), 4.14 (brs, 2H),3.8-3.4 (m, 12H), 2.27 (m, 2H), 1.86 (brs, 3H); ESIMS 569.9 (23) [MH⁺],285.6 (100). ESIMS 570.0 (24) [MH⁺], 285.5 (100). UV (MeOH): λ_(max)/nm(log ε)=238 (4.62), 205 (4.60).

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4yl]-2-[4-(4-trifluoromethylbenzyl)-[1,4]diazapan-1-yl]-acetamide(8.41): (18%) ¹H NMR (200 MHz, CDCl₃) δ 9.63 (s, 1H), 8.36 (m, 2H), 7.51(m, 7H), 7.21 (s, 1H), 6.62 (m, 1H), 5.53 (m, 1H), 3.75 (s, 2H), 3.67(m, 2H), 3.53 (m, 2H), 3.32 (s, 2H), 2.95-2.76 (m, 8H), 1.86 (m, 5H). MS(ES) 570 (M⁺). t_(R) (method B)=11.0 min

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4yl]-2-(4-pyridin-3-ylmethyl-[1,4]diazapan-1-yl)-acetamide(8.42): (82%) ¹H NMR (200 MHz, CDCl₃) δ 9.62 (s, 1H) 8.57 (s, 1H) 8.50(d, 1H, J=3 Hz) 8.35 (m, 2H), 7.73 (d, 1H, J=8 Hz) 7.47 (m, 3H) 7.21 (s,1H) 6.58 (m, 1H) 5.46 (m, 1H) 3.71 (m, 4H), 3.53 (m, 2H) 3.31 (s, 2H),2.90-2.76 (m, 8H), 1.86 (m, 5H). MS (ES) 503 (M⁺). t_(R) (method B)=6.8min.

N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-[4-(3-chlorobenzyl)-[1,4]diazepan-1-yl]-acetamide(8.43): Yield 99%. MS (ES): m/z 535.9/538.0 (57/19) [MH⁺]. ¹H NMR (200MHz, CDCl₃) δ 9.64 (s, 1H), 8.40-8.32 (m, 2H), 7.50-7.42 (m, 3H), 7.37(s, 1H), 7.26-7.20 (m, 4H), 6.52 (brs, 1H), 5.36 (brs, 1H), 3.75-3.62(m, 2H), 3.67 (s, 2H), 3.58-3.47 (m, 2H) 3.32 (s, 2H), 2.95-2.72 (m,8H), 1.96-1.85 (m, 2H), 1.86 (s, 3H). t_(R) (method A)=5.6 min.

N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-(4-pyridin-2-ylmethyl-[1,4]diazepan-1-yl)-acetamide(8.44): Yield 70%. MS (ES): m/z 502.9 (32) [MH⁺]. ¹H NMR (200 MHz,CDCl₃) δ 9.63 (s, 1H), 8.50 (dd, 1H, J=1.8, 4.8 Hz), 8.40-8.32 (m, 2H),7.66 (dt, 1H, J=1.8, 7.6 Hz), 7.55-7.44 (m, 4H), 7.24-7.12 (m, 1H), 7.21(s, 1H), 6.52 (brs, 1H) 5.34 (brs, 1H) 3.88 (s, 2H), 3.75-3.62 (m, 2H),3.58-3.47 (m, 2H) 3.32 (s, 2H), 2.95-2.80 (m, 8H), 2.00-1.85 (m, 2H),1.86 (s, 3H). t_(R) (method B)=9.4 min.

N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-[4-(6-methylpyridin-2-ylmethyl)-[1,4]diazepan-1-yl]-acetamide(8.45): Yield 93%. MS (ES): m/z 516.9 (23) [M⁺]. ¹H NMR (200 MHz, CDCl₃,200 MHz) δ 9.64 (s, 1H), 8.40-8.33 (m, 2H), 7.55 (t, 1H, J=7.9 Hz),7.50-7.42 (m, 3H), 7.34 (d, 1H, J=7.8 Hz), 7.22 (s, 1H), 7.02 (d, 1H,J=8.0 Hz), 6.52 (brs, 1H) 5.34 (brs, 1H) 3.85 (s, 2H), 3.75-3.62 (m,2H), 3.58-3.47 (m, 2H) 3.32 (s, 2H), 2.95-2.80 (m, 8H), 2.54 (s, 3H),2.00-1.85 (m, 2H), 1.86 (s, 3H). t_(R) (method B)=9.9 min.

N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-acetamide(8.46): MS (ES) 523.3/525.3 (70/25) [MH⁺].

EXAMPLE 5

Synthesis of Compounds 8.47-8.128 (for Library Format)

6-chloro-2-phenylpyrimidin-4-amine (4)

4,6-dichloro-2-phenylpyrimidine (3) (5.0 g) (literature reference:Biagi, Giuliana: Giorgi, Irene; Livi, Oreste; Scartoni, Valerio;Lucacchini, Antonio; Farmaco: 52; 1; 1997; 61-66) was dissolved in DMSO(50ml) in a sealable vessel. Ammonia gas was then bubbled through thesolution for 15 minutes, the vessel sealed and the reaction left to stirfor 24 hr. The solution was partitioned between ethyl acetate (200 ml)and water (200 ml) and the aqueous phase extracted with ethyl acetate(2×100 ml). The combined organic phases were washed with brine (100 ml),dried over anhydrous magnesium sulfate and concentrated in vacuo,affording the title compound (3.87 g).

δ_(H) (CDCl₃): 5.0 (2H, s), 6.38 (1H, s), 7.41-7.48 (3H, m), 8.35-8.38(2H, d); m/z (ES⁺) 206 (MH)⁺

2-Bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide (21)

6-chloro-2-phenylpyrimidin-4-amine (4) (830 mg) was dissolved inanhydrous DCM (50 ml). To this was added dropwise a solution ofbromoacetylbromide (1.05 ml in 10 ml DCM), forming a precipitate after10 min. To this was then added dropwise a solution ofN,N-diisopropylethylamine (1.06 ml in 10 ml DCM) and the solution leftfor 1 hr. The solvent was removed in vacuo, then the crude solidpurified by flash chromatography on silica gel eluting with a mixture ofethyl acetate and petroleum ether (1:9 then 1:1 v/v), furnishing thetitle compound as a solid (1.09 g).

δ_(H) (CDCl₃): 4.02 (2H, s), 7.42-7.52 (3H, m), 8.05 (1H, s), 8.35-8.42(2H, d), 8.75-8.80 (1H, s); m/z (ES⁺) 328 (MH)⁺

N-(6-chloro-2-phenylpyrimidin-4-yl)-2-piperidin-1-ylacetamide (22.47)

2-Bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide (28 mg) wasdissolved in acetonitrile (2 ml) and piperidine added (23 μl in 500 μlacetonitrile). The mixture was left to stir for 1.5 hr after which timethe solvent was removed in vacuo. Purification using a short silicaplug, eluting with a mixture of ethyl acetate and petroleum ether (1:1v/v) furnished the title compound (25 mg).

δ_(H) (CDCl₃): 1.48-1.52 (2H, m), 1.63-1.78 (4H, m), 2.50-2.60 (4H, m),3.15 (2H, s), 7.42-7.51 (3H, m), 8.14 (1H, s), 8.38-8.42 (2H, d); m/z(ES⁺) 331 (MH)⁺

N-(6-chloro-2-phenylpyrimidin-4-yl)-2-[4-(4-trifluromethyl-2-nitrophenyl)piperazin-1-yl]acetamide(22.48)

2-Bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide (100 mg) wasdissolved in acetonitrile (5 ml) and(4-trifluromethyl-2-nitrophenyl)piperazine (253 mg) added. The solutionwas stirred overnight at room temperature. After this time the solventwas removed in vacuo. Purification by flash chromatography on silica geleluting with a mixture of dichloromethane and methanol (98:2, then 93:7v/v) afforded the title compound. m/z (ES⁺) 521 (MH)⁺

Compounds 22.49-22.53 were synthesized in an analogous manner:

-   -   2-[4-(3-Chloro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide        (22.49): m/z (ES⁺) 511 (MH)⁺.    -   N-(6-Chloro-2-phenylpyrimidin-4-yl)-2-[4-(3-phenylpropyl)piperazin-1-yl]acetamide        (22.50): m/z (ES⁺) 450 (MH)⁺.    -   2-[4-(4-tert-Butylbenzyl)piperazin-1-yl]-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide        (22.51): m/z (ES⁺) 478 (MH)⁺.    -   N-(6-Chloro-2-phenylpyrimidin-4-yl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)acetamide        (22.52): m/z (ES⁺) 400 (MH)⁺.    -   N-(6-Chloro-2-phenylpyrimidin-4-yl)-2-(4-hydroxy-4-thien-2-ylpiperidin-1-yl)acetamide        (22.53): m/z (ES⁺) 411 (M+H−H₂O)⁺.        N-(6-Chloro-2-phenylpyrimidin-4-yl)-2-{4-[(2E)-3-phenylprop-2-enyl]piperazin-1-yl}acetamide        (22.54).

To a stirred solution of2-bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide (0.80 g in 40 mlacetonitrile) was added [(2E)-3-phenylprop-2-enyl]piperazine (0.50 g in10 ml acetonitrile). After 3 hrs, N,N-diisopropylethylamine was added(428 μl in 10 ml acetonitrile) and the reaction stirred for a further 2hrs after which time a precipitate of the title compound appeared. Thiswas used crude in the next step.

m/z (ES⁺) 448 (MH)⁺

Compound 22.55 was synthesised in an analogous manner:

-   -   N-(6-chloro-2-phenylpyrimidin-4-yl)-2-(4-benzylpiperidin-1-yl)acetamide        (22.55): m/z (ES⁺) 421 (MH)⁺.        N-(6-{([2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-piperidin-1-ylacetamide        (8.47)

N-(6-Chloro-2-phenylpyrimidin-4-yl)-2-piperidin-1-ylacetamide (25 mg)was dissolved in DMSO (1 ml) and N-acetylethylenediamine (78 mg) added.A reflux condenser was fitted and the mixture heated to 130° C. withstirring for 16 hrs. The reaction was cooled to room temperature and thesolvent removed in vacuo. Purification via flash chromatography onsilica gel, eluting with a mixture of dichloromethane and methanol(95:5, then 93:7 v/v) yielded the title compound (18 mg).

δH (CDCl₃): 1.50-1.58 (2H, m), 1.69-1.78 (4H, m), 1.89 (3H, s),2.50-2.60 (4H, m), 3.12 (2H, s), 3.51-3.58 (2H, m); 3.67-3.75 (2H, m),5.35-5.43 (1H, br s), 7.27 (1H, s), 7.48-7.52 (3H, m), 8.36-8.42 (2H,m), 9.61 (1H, s); m/z⁻(ES⁺) 397 (MH)⁺

Compounds 8.48-8.55 were synthesised in an analogous manner apart fromwhere otherwise indicated:

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[2-nitro-4-(trifluoromethyl)phenyl]piperazin-1-yl}acetamide(8.48): 59 mg over 2 steps from 100 mg2-bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide.

δ_(H) (CDCl₃): 1.86 (3H, s), 2.75-2.80 (4H, m), 3.20-3.28 (6H, m),3.48-3.52 (2H, m), 3.61-3.69 (2H, br m), 5.90-5.98 (1H, br s), 6.68-6.83(1H, br s), 7.20 (2H, s), 7.41-7.47 (3H, m), 7.65-7.70 (1H, d), 8.05(1H, s), 8.30-8.35 (2H, m), 9.33 (1H, s); m/z (ES⁺) 587 (MH)⁺

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}acetamide(8.49): 47 mg over 2 steps from 100 mg2-bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide.

δ_(H) (CDCl₃): 1.85 (3H, s), 2.73-2.81 (4H, m), 3.22 (2H, s), 3.49-3.55(2H, m), 3.59-3.71 (6H, m), 5.75-5.79 (1H, m), 6.64-6.78 (1H, br s),7.20 (1H, s), 7.42-7.47 (3H, m), 7.77 (1H, s), 8.30-8.37 (2H, m), 8.40(1H, s), 9.45 (1H, s); m/z (ES⁺) 577 (MH)⁺

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(3-phenylpropyl)piperazin-1-yl]acetamide(8.50): Purification via reverse phase HPLC (6 mg over 2 steps from 100mg 2-bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide.)

δ_(H) (CDCl₃): 2.12 (3H, s), 2.08-2.16 (2H, m), 2.66-2.74 (2H, m),2.98-3.10 (6H, m), 3.42-3.66 (m, 8H), 3.81-3.88 (2H, m), 6.78-6.84 (1H,br s), 7.12-7.16 (2H, d), 7.20-7.26 (2H, m), 7.28-7.32 (2H, t),7.56-7.62 (2H, m), 7.64-7.72 (1H, m), 8.06-8.12 (2H, d), 8.28-8.32 (1H,br s), 8.58-8.62 (1H, br s); m/z (ES⁻) 514 (M−H)⁻

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4-tert-butylbenzyl)piperazin-1-yl]acetamide(8.51): 19 mg over 2 steps from 100 mg2-bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide.

δ_(H) (CDCl₃): 1.30 (9H, s), 1.85 (3H, s), 2.50-2.68 (11H, m), 3.14 (2H,s), 3.48-3.52 (4H, m), 3.62-3.70 (2H, m), 5.50-5.60 (1H, m), 6.55-6.70(1H, br s), 7.20 (1H, s), 7.21-7.27 (2H, d), 7.32-7.37 (2H, d),7.43-7.48 (3H, m), 8.32-8.38 (2H, m), 9.45 (1H, s); m/z (ES⁻) 542 (M−H)⁻

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4-pyrrolidin-1-yl-piperidin-1-yl)acetamide(8.52): Reaction conducted at 100° C. (27 mg over 2 steps from 100 mg2-bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide.

δ_(H) (CDCl₃): 1.72-1.87 (7H, m), 1.92-2.10 (4H, m), 2.24-2.32 (2H, t),2.58-2.65 (4H, br, s), 2.87-2.95 (2H, d), 3.10 (2H, s), 3.33 (1H, s),3.46-3.52 (2H, m), 3.61-3.70 (2H, m), 5.68-5.72 (1H, m), 6.73-6.83 (1H,br s), 7.18 (1H, s), 7.40-7.48 (3H, m), 8.32-8.38 (2H, m), 9.50 (1H, s);m/z (ES⁺) 466 (MH)⁺

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4-hydroxy-4-thien-2-ylpiperidin-1-yl)acetamide(8.53): 9 mg over 2 steps from 100 mg2-bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide.

δ_(H) (CDCl₃): 1.74-1.89 (4H, m), 2.03-2.11 (2H, d), 2.25-2.35 (2H, m),2.73-2.85 (4H, m), 3.21 (2H, s), 3.48-3.55 (2H, m), 3.61-3.72 (2H, m),5.62 (1H, s), 6.57-6.71 (1H, br s), 7.00 (1H, m), 7.04-7.07 (1H, m),7.22 (1H, s), 7.25 (1H, s), 7.42-7.47 (3H, m), 8.31-8.37 (2H, m), 9.47(1H, s); m/z (ES⁺) 495 (MH)⁺

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[(2E)-3-phenylprop-2-enyl]piperazin-1-yl}acetamide(8.54): Reaction conducted at 100° C. for 3 hrs. Sample recrystallizedfrom methanol (354 mg over 2 steps from 0.80 g2-bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide).

δ_(H) (CDCl₃): 1.83 (3H, s), 2.59-2.75 (8H, br s), 3.17 (2H, s), 3.22(2H, d), 3.45-3.54 (2H, m), 3.62-3.70 (2H, m), 5.38-5.42 (1H, m),6.23-6.32 (1H, m), 6.40-6.52 (1H, br s), 6.52-6.59 (1H, d), 7.21-7.24(2H, m), 7.28-7.34 (2H, t), 7.35-7.40 (2H, d), 7.43-7.49 (3H, m),8.38-8.40 (2H, m), 9.43 (1H, s); m/z (ES⁺) 514 (MH)⁺

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4-benzylpiperidin-1-yl)acetamide(8.55): Reaction conducted at 100° C. for 3 hrs. (546 mg over 2 stepsfrom 0.80 g 2-bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide).

δ_(H) (CDCl₃): 1.42-1.50 (2H, t), 1.56 (1H, s), 1.66-1.74 (2H, br d),1.84-1.86 (3H, s), 2.18-2.24 (2H, t), 2.58-2.62 (2H, d), 2.84-2.91 (2H,d), 3.10 (2H, s), 3.50-3.56 (2H, m), 3.64-3.72 (2H, m), 5.36-5.40 (1H,m), 7.14-7.21 (3H, m), 7.22 (1H, s), 7.28-7.32 (2H, t), 7.46-7.50 (3H,m), 8.35-8.40 (2H, m), 9.50 (1H, s); m/z (ES⁺) 487 (MH)⁺

N-{2-[(6-amino-2-phenylpyrimidin-4-yl)amino]ethyl}acetamide (5):

6-Chloro-2-phenylpyrimidin-4-amine (2.87 g) was dissolved in DMSO (50ml) and N-acetylethylenediamine (14.28 g) added. The stirred solutionwas heated at 130° C. for 8 hrs then partitioned between ethyl acetate(500 ml) and saturated brine solution (400 ml). The organic phase wasdried over magnesium sulfate, filtered and the solvent removed in vacuo.Purification by flash chromatography on silica gel eluting with firstethyl acetate then a mixture of ethyl acetate and methanol (9:1 then 8:2v/v) yielded the title compound (2.50 g).

δ_(H) (CDCl₃): 1.82 (3H, s), 3.41-3.44 (2H, m), 3.52-3.59 (2H, m), 4.62(2H, s), 4.98-5.04 (1H, m), 6.57-6.65 (1H, br s), 7.41-7.43 (3H, m),8.29-8.34 (2H, m); m/z (ES⁺) 272 (MH)⁺

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-bromoacetamide(23)

To N-{2-[(6-amino-2-phenylpyrimidin-4-yl)amino]ethyl}acetamide (5) (1.20g) in anhydrous dichloromethane (100 ml) was added triethylamine (1.23ml), then bromoacetylbromide (768 μl) in 2 aliquots. The mixture wasleft to stir at room temperature for 10 mins then was partitionedbetween dichloromethane (50 ml) and water (50 ml). The aqueous layer wasextracted with dichloromethane (3×50 ml) and the organic layerscombined, dried over magnesium sulfate and filtered. The solvent wasremoved in vacuo and the resulting solid purified via columnchromatography on silica gel eluting with a mixture of ethyl acetate andpetrol ether (1:1 v/v), then ethyl acetate, then a mixture of ethylacetate and methanol (95:5 v/v) to furnish the title compound (195 mg).

δ_(H) (d⁶-acetone): 1.84 (3H, s), 3.35-3.44 (2H, m), 3.50-3.60 (2H, m),4.04 (2H, s), 6.18-6.23 (1H, br s), 6.68-6.75 (1H, br s), 7.11 (1H, s),7.48-7.51 (3H, m), 8.35-8.40 (2H, m), 8.97-9.04 (1H, br s); m/z (ES⁺)392 (MH)⁺

Example of Library Method:

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]acetamide(8.56):

N-(6-{[2-(Acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-bromoacetamide(23) (30 μl of a 0.167M solution) was dispensed to a well of a 96 wellmicrotitre plate, followed by [4-(4-bromophenyl)-4-hydroxypiperidine](30 μl of a 0.167M solution) and N,N-diisopropylethylamine (30 μl of a0.167M solution). The plate was placed in an oven at 63° C. for 5 hrs.The solvent was removed in vacuo yielding the title compound.

LCMS (Method A) RT=2.43 min, m/z (ES⁺) 569 (MH)⁺

The following compounds 8.57-8.128 were synthesized in an analogousmanner: Mass ion Retention (ES⁺) Name time (min) (MH)⁺N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4- 2.32533 hydroxy-4-(4-methoxybenzyl)piperidin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 2.36504 methoxyphenyl)piperazin-1-yl]acetamide tert-butyl4-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.47 498yl)amino]-2-oxoethyl}piperazine-1-carboxylateN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 1.93442 hydroxyethyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2,4-2.37 534 dimethoxyphenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(3- 1.96413 hydroxypiperidin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[2-(2-2.00 486 hydroxyethoxy)ethyl]piperazin-1-yl}acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.26476 pyrimidin-2-ylpiperazin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(3- 1.97456 hydroxypropyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4- 2.33533 hydroxy-4-(3-methoxybenzyl)piperidin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[3- 2.01427 (hydroxymethyl)piperidin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.47474 phenylpiperazin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 2.52492 fluorophenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 2.60519 nitrophenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 2.40516 acetylphenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.08475 pyridin-2-ylpiperazin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 2.50492 fluorophenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[3- 2.45543 (trifluoromethyl)pyridin-2-yl]piperazin-1-yl}acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4- 2.00427 (hydroxymethyl)piperidin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 2.41519 fluorobenzoyl)piperidin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(3,5-2.49 543 dichloropyridin-4-yl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 2.45503 methoxyphenyl)piperidin-1-yl]acetamide1-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino]-1.95 440 2-oxoethyl}piperidine-4-carboxamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(3- 2.49504 methoxyphenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 2.40504 methoxyphenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 2.68508 chlorophenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2,4-2.66 502 dimethylphenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.25476 pyrimidin-2-ylpiperazin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(3,4-2.86 542 dichlorophenyl)piperazin-1-yl]acetamideN-(6{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 2.24490 hydroxyphenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(3- 2.67508 chlorophenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(3,4-2.55 502 dimethylphenyl)piperazin-1-yl]acetamide1-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino]-2.22 496 2-oxoethyl}-piperidine-3-carboxylic acid diethyl amideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 2.30492 furoyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2,5-2.63 502 dimethylphenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.32494 cycloheptylpiperazin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.02426 ethylpiperazin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(1,3-2.28 532 benzodioxol-5-ylmethyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.07440 acetylpiperazin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[bis(4-2.68 600 fluorophenyl)methyl]piperazin-1-yl}acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.57564 benzhydrylpiperazin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[(4-2.73 598 chlorophenyl)(phenyl)methyl]piperazin-1-yl}acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 2.32516 phenylethyl)-1,4-diazepan-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(2- 2.16411 methylpiperidin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.06438 allylpiperazin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.19466 cyclopentylpiperazin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 2.36521 fluorobenzyl)-4-hydroxypiperidin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 2.37502 phenylethyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 2.06456 methoxyethyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 2.37522 chlorobenzyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}2-phenylpyrimidin-4-yl)-2-[4-(2- 2.07509 oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.43487 benzylpiperidin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.59498 cyano-4-phenylpiperidin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(3,4- 2.32445 dihydroisoquinolin-2(1H)-yl)acetamide ethyl4-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.30 470yl)amino]-2-oxoethyl}piperazine-1-carboxylateN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.26498 hydroxy-4-phenylpiperidin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.20476 pyrazin-2-ylpiperazin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4- 2.42557 hydroxy-4-[3-(trifluoromethyl)phenyl]piperidin-1-yl}acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.37515 acetyl-4-phenylpiperidin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4- 2.50579 [hydroxy(diphenyl)methyl]piperidin-1-yl}acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4-oxo-1-2.32 543 phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[4- 2.56591 chloro-3-(trifluoromethyl)phenyl]-4-hydroxypiperidin-1-yl}acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2- 2.04 399morpholin-4-ylacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 2.40517 methoxyphenyl)-3-methylpiperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[2- 1.96521 (diallylamino)ethyl]piperazin-1-yl}acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.26480 cyclohexylpiperazin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 2.31490 hydroxyphenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[3- 2.57502 methyl-4-(3-methylphenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-azepan-2.18 411 1-ylacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(3- 2.32520 fluorobenzyl)-4-hydroxypiperidin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[3- 2.50502 methyl-4-(4-methylphenyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 2.48499 cyanophenyl)piperazin-1-yl]acetamide

EXAMPLE 6

Synthesis of Oxalamides 26.1-26.79

Methyl[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)acetate(24)

N-{2-[(6-Amino-2-phenylpyrimidin-4-yl)amino]ethyl}acetamide (5) (500 mg)was dissolved in anhydrous dichloromethane (10 ml) with stirring andcooled to 0° C. using an ice bath. To this was added dropwise a solutionof methyl oxalyl chloride (170 μl in 5 ml anhydrous dichloromethane) andthe reaction left to warm to room temperature over 3 hrs. The solventwas removed in vacuo and the mixture purified via column chromatographyon silica gel eluting with a mixture of dichloromethane and methanol(95:5 v/v) to reveal the title compound (247 mg).

δ_(H) (d⁶-DMSO): 1.87 (3H, s), 3.50-3.58 (2H, m), 3.63-3.77 (2H, m),3.98 (3H, s), 5.58-5.62 (1H, br s), 7.20 (1H, s), 7.42-7.48 (3H, m),8.32-8.37 (2H, m), 9.21 (1H, s); m/z (ES⁺) 358 (MH)⁺

[(6-{[2-(Acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)aceticacid (25)

Methyl[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)acetate(10 mg) was dissolved in anhydrous THF (1.5 ml) and potassiumtrimethylsilanate (4 mg) added. The reaction was left for 3 hrs afterwhich time a precipitate of the title compound was visible which wasfiltered (10 mg).

m/z (ES⁺) 344 (MH)⁺

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2-piperidin-1-ylacetamide(26.1)

To a stirred solution of[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)aceticacid (50 mg) in NMP (2.5 ml) were added HATU (51 mg) andN,N-diisopropylethylamine (25 μl). The mixture was stirred at roomtemperature for 15 min then piperidine (90 μl) added and the solutionleft for 16 hrs. After this time, the solvent was removed in vacuo.Purification via flash chromatography on silica gel using ethyl acetateas the eluent furnished the correct material (10 mg).

δ_(H) (CD₃CN): 1.52-1.70 (6H, m), 1.79 (3H, s), 3.33-3.39 (2H, q),3.42-3.68 (6H, br m), 6.10-6.18 (1H, br s), 6.58-6.62 (1H, br s),7.05-7.15 (1H, br s), 7.42-7.48 (3H, m), 8.35-8.40 (2H, m), 9.11-9.20(1H, br s); m/z (ES⁺) 411 (MH)⁺

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4-benzylpiperidin-1-yl)-2-oxoacetamide(26.2)

Methyl[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)acetate(50 mg) was dissolved in DMSO (420 μl) with stirring. To this were added4-benzylpiperidine (74 μl) and activated powdered 4 angstrom molecularsieves and the mixture left to stir at room temperature for 5 hrs. Afterthis time the reaction was filtered and first dichloromethane (1.6 ml)then PS-NCO (0.58 g) were added and the mixture left to stir for 1 hr.The resulting slurry was filtered, then partitioned betweendichloromethane (20 ml) and water (20 ml), and the aqueous layerextracted with dichloromethane (2×20 ml). The combined organics weredried over magnesium sulfate, filtered and the solvent removed in vacuo.Further purification via column chromatography on silica gel elutingwith a mixture of dichloromethane and methanol (94:6 v/v) furnished thetitle compound (33 mg).

δ_(H) (CDCl₃): 1.20-1.40 (2H, m), 1.57 (1H, s), 1.72-1.90 (5H, m),2.54-2.60 (2H, m), 2.66-2.76 (1H, t), 3.01-3.10 (1H, t), 3.48-3.56 (2H,m), 3.63-3.72 (2H, m), 4.52-4.59 (1H, d), 4.81-4.90 (1H, d), 5.38-5.42(1H, br s), 7.10-7.16 (3H, m), 7.18-7.24 (1H, m), 7.24-7.32 (2H, m),7.41-7.48 (3H, m), 8.30-8.36 (2H, m), 9.30-9.36 (1H, br s); m/z (ES⁺)501 (MH)⁺

Library Example:

N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2-(4-phenylpiperazin-1-yl)acetamide(26.3)

To a well of a 96 well microtitre plate were added methyl[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)acetate(30 μl of a 0.3M solution in anhydrous DMSO) and 4-phenylpiperazine (30μl of a 1.5M solution). This solution was left to shake on a plateshaker for 16 hrs. After this time 800 μl of dichloromethane were added,then 100 mg of PS-NCO. The plate was sealed, then mixed for 48 hrs. Theslurry was filtered and the solvents removed in vacuo, to furnish thetitle compound.

LCMS (Method B) RT=2.04 min, m/z (ES⁺) 488 (MH)⁺

The following compounds 26.4-26.79 were synthesized in an analogousmanner: Retention Mass Ion Name time (min) (ES⁺) (MH)⁺N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 2.10506 fluorophenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 1.99530 acetylphenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 2.08506 fluorophenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 1.88503 hydroxy-4-phenylpiperidin-1-yl)-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 2.28556 {4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 2.14557 {4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(3,5-2.02 557 dichloropyridin-4-yl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2,5-2.26 516 dimethylphenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 1.97518 methoxyphenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 1.37426 methylpiperazin-1-yl)-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 1.98518 methoxyphenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 1.35456 hydroxyethyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(1,3-2.09 544 benzothiazol-2-yl)piperidin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(3- 1.40470 hydroxypropyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(3,4-2.14 516 dimethylphenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.21501 benzylpiperazin-1-yl)-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 1.44440 ethylpiperazin-1-yl)-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 1.67454 acetylpiperazin-1-yl)-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 1.65528 {4-[(2E)-3-phenylprop-2-enyl]piperazin-1-yl}acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 1.42452 allylpiperazin-1-yl)-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 1.50480 cyclopentylpiperazin-1-yl)-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 1.62508 cycloheptylpiperazin-1-yl)-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 1.60516 [4-(2-phenylethyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 1.42470 methoxyethyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 1.68536 chlorobenzyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[2- 1.41483 (dimethylamino)ethyl]piperazin-1-yl}-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 1.93517 benzyl-4-hydroxypiperidin-1-yl)-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 1.86532 methoxyphenyl)-3-methylpiperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 1.46489 (4-pyridin-4-ylpiperazin-1-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(3- 1.85504 hydroxyphenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 1.92504 hydroxyphenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 1.48523 [4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 2.08513 cyanophenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[(2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4- 1.64441 (hydroxymethyl)piperidin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 1.62427 hydroxypiperidin-1-yl)-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[2-(2- 1.77455 hydroxyethyl)piperidin-1-yl]-2-oxoacetamide ethyl1-[[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 1.94 483yl)amino](oxo)acetyl]piperidine-4-carboxylateN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 1.42480 (4-pyrrolidin-1-ylpiperidin-1-yl)acetamide1-[[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 1.57 454yl)amino](oxo)acetyl]piperidine-4-carboxamide1-[[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 1.85 510yl)amino](oxo)acetyl]-piperidine-3-carboxylic acid diethylamide ethyl1-[[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 1.96 483yl)amino](oxo)acetyl]piperidine-3-carboxylate1-[[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 1.66 454yl)amino](oxo)acetyl]piperidine-3-carboxamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[3- 1.69441 (hydroxymethyl)piperidin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(3- 1.67427 hydroxypiperidin-1-yl)-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2- 1.72 413morpholin-4-yl-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-azepan-1.93 425 1-yl-2-oxoacetamideN1-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-N2- 2.02 447benzyl-N2-methylethanediamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(3,4- 2.06459 dihydroisoquinolin-2(1H)-yl)-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2,4-2.17 524 difluorophenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(6- 1.53503 methylpyridin-2-yl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 2.11502 methylphenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 2.03513 cyanophenyl)piperazin-1-yl]-2-oxoacetamideN1-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-N2- 2.03 461methyl-N2-(2-phenylethyl)ethanediamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 1.82397 pyrrolidin-1-ylacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4- 2.09512 cyano-4-phenylpiperidin-1-yl)-2-oxoacetamideN1-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-N2-(2- 1.71410 cyanoethyl)-N2-methylethanediamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2,4-1.92 548 dimethoxyphenyl)piperazin-1-yl]-2-oxoacetamideN1-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-N2- 1.36 454methyl-N2-(1-methylpiperidin-4-yl)ethanediamideN1-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-N2,N2- 2.03423 diallylethanediamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 1.56480 [2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]acetamideN1-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-N2-[2- 1.38428 (dimethylamino)ethyl]-N2-methylethanediamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2,6-2.30 516 dimethylphenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 1.90415 (1,3-thiazolidin-3-yl)acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(2,6- 1.84441 dimethylmorpholin-4-yl)-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4- 2.06532 ethoxyphenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(3- 1.96535 fluorobenzyl)-4-hydroxypiperidin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(2- 2.27516 ethylphenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 1.66530 [4-(3-phenylpropyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 1.42509 [4-(2-pyrrolidin-1-ylethyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 1.61530 [4-(2-phenylethyl)-1,4-diazepan-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[3- 2.07516 methyl-4-(3-methylphenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(1,3-1.60 546 benzodioxol-5-ylmethyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(3,5-2.10 548 dimethoxyphenyl)piperazin-1-yl]-2-oxoacetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 1.68510 [4-(tetrahydrofuran-2-ylcarbonyl)piperazin-1-yl]acetamideN-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-oxo-2- 1.52489 (4-pyridin-2-ylpiperazin-1-yl)acetamideN-(1-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 1.88 530yl)amino]-2-oxoacetyl}piperidin-4-yl)benzamide

EXAMPLE 7

Synthesis of Compounds 29.1-29.146

N-{2-[(6-Chloro-2-phenylpyrimidin-4-yl)amino]ethyl}acetamide (27)

4,6-Dichloro-2-phenylpyrimidine (3) (5.59 g), N-acetylethylenediamine(2.79 g) and N,N-diisopropylethylamine (3.53 g) were added topropan-1-ol (50 ml). A calcium drying tube was fitted and the resultingsuspension heated to reflux for 34 hrs, then left to cool to ambienttemperature. The resulting solution was evaporated in vacuo onto silicagel (40 g) and purified by flash chromatography eluting with ethylacetate then a mixture of ethyl acetate and methanol (10:1 v/v) tofurnish the title compound (6.79 g).

δ_(H) (CDCl₃): 1.92 (3H, s), 3.43-3.52 (2H, m), 3.54-3.64 (2H, br s),5.70-5.78 (1H, br s), 6.28 (1H, s), 7.41-7.46 (3H, m), 8.37-8.40 (2H,d); m/z (ES⁺) 291 (MH)⁺

N-{2-[(2-Phenyl-6-piperazin-1-ylpyrimidin-4-yl)amino]ethyl}acetamide(28)

N-{2-[(6-Chloro-2-phenylpyrimidin-4-yl)amino]ethyl}acetamide (27) (1.5g) and piperazine (4.44 g) were dissolved in DMSO. To this was addedsodium hydrogencarbonate (2.16 g) and the mixture heated to 110° C. for3 hrs. The reaction mixture was cooled to ambient temperature thenpartitioned between ethyl acetate (150 ml) and water (150 ml). Theaqueous layer was washed with ethyl acetate (2×200 ml) and the combinedorganics washed with brine (100 ml), dried over magnesium sulfate thenfiltered. Removal of the solvent in vacuo furnished the title compound(0.865 g).

δ_(H) (CDCl₃): 1.81 (3H, s), 2.92-2.98 (4H, m), 3.42-3.48 (2H, m),3.58-3.63 (6H, m), 4.90-4.95 (1H, m), 5.43 (1H, s), 6.80-6.85 (1H br s),7.40-7.43 (3H, m), 8.33-8.38 (2H, m); m/z (ES⁺) 341 (MH)⁺

N-(2-{[6-(4-Benzoylpiperazin-1-yl)-2-phenylpyrimidin-4-yl]amino}ethyl)acetamide(29.1)

A solution of benzoic acid (18 mg), HATU (51 mg) anddiisopropylethylamine (26 μl) in NMP (2 ml) was stirred at ambienttemperature for 5 min thenN-{2-[(2-phenyl-6-piperazin-1-ylpyrimidin-4-yl)amino]ethyl}acetamide (50mg in 1 ml NMP) was added and the mixture stirred for a further 1.5 hr.Purification via ion exchange silica (SCX) yields the title compound onevaporation of the solvent (25 mg).

LC retention time: 2.55 min; m/z (ES⁺) 445 (MH)⁺

Library Example:

N-[2-({2-Phenyl-6-[4-(quinolin-2-ylcarbonyl)piperazin-1-yl]pyrimidin-4-yl}amino)ethyl]acetamide(29.2)

A solution of quinaldic acid (30 μl of a 0.3M solution in NMP), HATU (30μl of a 0.3M solution in NMP) and diisopropylethylamine (30 μl of a 0.3Msolution in NMP) was shaken at ambient temperature in a well of a 96position microtitre plate for 10 min.N-{2-[(2-phenyl-6-piperazin-1-ylpyrimidin-4-yl)amino]ethyl}acetamide (30μl of a 0.3M solution in NMP) was then added and the mixture shaken fora further 12 hr. Purification via ion exchange silica (SCX) yields thetitle compound.

LCMS (Method A) RT=2.45 min; m/z (ES⁺) 497 (MH)⁺

The following compounds 29.3-29.146 were made in an analogous manner:Mass ion Retention (ES⁺) Name Time (min) (MH)⁺N-[2-({6-[4-(isoquinolin-3-ylcarbonyl)piperazin-1-yl]-2-phenylpyrimidin-2.42 496 4-yl}amino)ethyl]acetamideN-[2-({2-phenyl-6-[4-(quinoxalin-2-ylcarbonyl)piperazin-1-yl]pyrimidin-4-2.43 497 yl}amino)ethyl]acetamideN-[2-({6-[4-(isoquinolin-1-ylcarbonyl)piperazin-1-yl]-2-phenylpyrimidin-2.41 496 4-yl}amino)ethyl]acetamideN-[2-({6-[4-(2-hydroxy-5-nitrobenzoyl)piperazin-1-yl]-2-phenylpyrimidin-2.39 506 4-yl}amino)ethyl]acetamideN-[2-({6-[4-(2,5-dihydroxybenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4-2.32 477 yl}amino)ethyl]acetamideN-[2-({2-phenyl-6-[4-(pyrazin-2-ylcarbonyl)piperazin-1-yl]pyrimidin-4-2.17 447 yl}amino)ethyl]acetamideN-(2-{[6-(4-isonicotinoylpiperazin-1-yl)-2-phenylpyrimidin-4- 2.10 446yl]amino}ethyl)acetamideN-{2-[(6-{4-[(2-hydroxypyridin-3-yl)carbonyl]piperazin-1-yl}-2- 2.41 462phenylpyrimidin-4-yl)amino]ethyl}acetamideN-[2-({6-[4-(1H-indol-2-ylcarbony)piperazin-1-yl]-2-phenylpyrimidin-4-2.58 484 yl}amino)ethyl]acetamideN-[2-({6-[4-(1H-indol-3-ylcarbonyl)piperazin-1-yl]-2-phenylpyrimidin-4-2.40 484 yl}amino)ethyl]acetamideN-[2-({6-[4-(3-nitrobenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.46490 yl}amino)ethyl]acetamideN-{2-[(6-{4-[(4-acetyl-5-methyl-2-oxo-2,3-dihydro-1H-pyrrol-3- 2.24 520yl)acetyl]piperazin-1-yl}-2-phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(3-hydroxy-4-methoxyphenyl)acetyl]piperazin-1-yl}-2- 2.41505 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(2E)-3-(1H-indol-3-yl)prop-2-enoyl]piperazin-1-yl}-2- 2.52510 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(2E)-3-(3-nitrophenyl)prop-2-enoyl]piperazin-1-yl}-2- 2.55516 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-[2-({6-[4-(2-hydroxy-4-methylbenzoyl)piperazin-1-yl]-2- 2.42 475phenylpyrimidin-4-yl}amino)ethyl]acetamideN-[2-({6-[4-(2-hydroxy-3-methoxybenzoyl)piperazin-1-yl]-2- 2.36 492phenylpyrimidin-4-yl}amino)ethyl]acetamideN-[2-({6-[4-(2-hydroxy-3-methylbenzoyl)piperazin-1-yl]-2- 2.48 475phenylpyrimidin-4-yl}amino)ethyl]acetamideN-[2-({6-[4-(1H-indol-3-ylacetyl)piperazin-1-yl]-2-phenylpyrimidin-4-2.45 498 yl}amino)ethyl]acetamideN-{2-[(6-{4-[3-(1H-indol-3-yl)propanoyl]piperazin-1-yl}-2- 2.49 512phenylpyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-phenyl-6-[4-(pyridin-2-ylcarbonyl)piperazin-1-yl]pyrimidin-4-2.48 446 yl}amino)ethyl]acetamideN-{2-[(6-{4-[4-(1H-indol-3-yl)butanoyl]piperazin-1-yl}-2-phenylpyrimidin-2.59 526 4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(5-methylpyrazin-2-yl)carbonyl]piperazin-1-yl}-2- 2.24 461phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)carbonyl]piperazin-2.71 526 1-yl}-2-phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3- 2.28 503yl)carbonyl]piperazin-1-yl}-2-phenylpyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-(4-{[2-(methylsulfanyl)pyridin-3-yl]carbonyl}piperazin-1-yl)-2-2.37 492 phenylpyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(6-{4-[(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)carbonyl]piperazin-1-2.45 505 yl}-2-phenylpyrimidin-4-yl)amino]ethyl}acetamideN-[2-({6-[4-(1-benzothien-2-ylcarbonyl)piperazin-1-yl]-2- 2.62 501phenylpyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(2-phenyl-6-{4-[4-(trifluoromethoxy)benzoyl]piperazin-1- 2.64 529yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(5-chloro-2-hydroxypyridin-3-yl)carbonyl]piperazin-1-yl}-2-2.39 496 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(2E)-4-oxo-4-(2,3,4,5,6-pentamethylphenyl)but-2- 2.81 569enoyl]piperazin-1-yl}-2-phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-phenyl-6-{4-[4-(trifluoroacetyl)benzoyl]piperazin-1-yl}pyrimidin-2.39 541 4-yl)amino]ethyl}acetamideN-{2-[4-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.46 536yl)piperazin-1-yl]-2-oxoethyl}-4-chlorobenzamideN-{2-[(6-{4-[(2,4-dihydroxypyrimidin-5-yl)carbonyl]piperazin-1-yl}-2-2.01 479 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-phenyl-6-[4-(1,2,3-thiadiazol-4-ylcarbonyl)piperazin-1- 2.44453 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-(2-{[6-(4-{[5-chloro-2-(methylsulfanyl)pyrimidin-4- 2.52 527yl]carbonyl}piperazin-1-yl)-2-phenylpyrimidin-4-yl]amino}ethyl)acetamideN-(2-{[6-(4-{[1-(2-furylmethyl)-5-oxopyrrolidin-3-yl]carbonyl}piperazin-1-2.33 532 yl)-2-phenylpyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(6-{4-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]piperazin-1-2.55 505 yl}-2-phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(4-nitrophenyl)acetyl]piperazin-1-yl}-2-phenylpyrimidin-4-2.49 504 yl)amino]ethyl}acetamideN-{2-[(6-{4-[(2,5-dimethoxyphenyl)acetyl]piperazin-1-yl}-2- 2.48 519phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(3-methoxyphenyl)acetyl]piperazin-1-yl}-2-phenylpyrimidin-2.45 489 4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(4-methoxyphenyl)acetyl]piperazin-1-yl}-2-phenylpyrimidin-2.44 490 4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(2-methoxyphenyl)acetyl]piperazin-1-yl}-2-phenylpyrimidin-2.47 489 4-yl)amino]ethyl}acetamideN-[2-({2-phenyl-6-[4-(1,2,3,4-tetrahydronaphthalen-2- 2.65 499ylcarbonyl)piperazin-1-yl]pyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(6-{4-[(2R)-2-hydroxy-3-phenylpropanoyl]piperazin-1-yl}-2- 2.40489 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-phenyl-6-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]pyrimidin-4-2.54 434 yl}amino)ethyl]acetamideN-[2-({2-phenyl-6-[4-(4-vinylbenzoyl)piperazin-1-yl]pyrimidin-4- 2.54471 yl}amino)ethyl]acetamideN-[2-({6-[4-(cyclohexylacetyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.61465 yl}amino)ethyl]acetamideN-{2-[(2-phenyl-6-{4-[4-(1H-pyrrol-1-yl)benzoyl]piperazin-1-yl}pyrimidin-2.63 510 4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2- 2.47 542yl)propanoyl]piperazin-1-yl}-2-phenylpyrimidin-4-yl)amino]ethyl}acetamideN-[2-({6-[4-([1,1′-biphenyl]-4-ylacetyl)piperazin-1-yl]-2-phenylpyrimidin-2.78 536 4-yl}amino)ethyl]acetamideN-{2-[(6-{4-[(6-methoxy-3-oxo-2,3-dihydro-1H-inden-1- 2.41 543yl)acetyl]piperazin-1-yl}-2-phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(3-nitrophenyl)acetyl]piperazin-1-yl}-2-phenylpyrimidin-4-2.51 504 yl)amino]ethyl}acetamideN-{2-[(6-{4-[(2-methylphenyl)acetyl]piperazin-1-yl}-2-phenylpyrimidin-4-2.53 473 yl)amino]ethyl}acetamideN-{2-[(6-{4-[(4-methylphenyl)acetyl]piperazin-1-yl}-2-phenylpyrimidin-4-2.55 473 yl)amino]ethyl}acetamideN-[2-({6-[4-(3-methylbenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.69459 yl}amino)ethyl]acetamideN-[2-({6-[4-(4-methylbenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.50459 yl}amino)ethyl]acetamideN-[2-({6-[4-(2-methylbenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.45459 yl}amino)ethyl]acetamideN-{2-[(6-{4-[(3-methylphenyl)acetyl]piperazin-1-yl}-2-phenylpyrimidin-4-2.53 473 yl)amino]ethyl}acetamideN-[2-({6-[4-(4-butylbenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.81501 yl}amino)ethyl]acetamideN-[2-({6-[4-(4-nitrobenzoyl)piperazin-1-yl]-2--phenylpyrimidin-4- 2.45490 yl}amino)ehyl]acetamideN-[2-({6-[4-(2-phenoxypropanoyl)piperazin-1-yl]-2-phenylpyrimidin-4-2.50 489 yl}amino)ethyl]acetamideN-{2-[(6-{4-[(3,4-dihydroxyphenyl)acetyl]piperazin-1-yl}-2- 2.40 491phenylpyrimidin-4-yl)amino]ethyl}acetamideN-[2-({6-[4-(1,3-benzodioxol-5-ylcarbonyl)piperazin-1-yl]-2- 2.39 489phenylpyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-phenyl-6-[4-(phenylacetyl)piperazin-1-yl]pyrimidin-4- 2.42 459yl}amino)ethyl]acetamideN-[2-({6-[4-(bicyclo[2.2.1]hept-5-en-2-ylcarbonyl)piperazin-1-yl]-2-2.45 461 phenylpyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(6-{4-[hydroxy(phenyl)acetyl]piperazin-1-yl}-2-phenylpyrimidin-4-2.33 475 yl)amino]ethyl}acetamideN-{2-[(6-{4-[(2-naphthyloxy)acetyl]piperazin-1-yl}-2-phenylpyrimidin-4-2.69 525 yl)amino]ethyl}acetamideN-{2-[(2-phenyl-6-{4-[(1-phenylcyclopentyl)carbonyl]piperazin-1- 2.76513 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-phenyl-6-[4-(2-sulfanylbenzoyl)piperazin-1-yl]pyrimidin-4- 2.68477 yl}amino)ethyl]acetamideN-{2-[(6-{4-[cyclopentyl(phenyl)acetyl]piperazin-1-yl}-2-phenylpyrimidin-2.84 527 4-yl)amino]ethyl}acetamideN-[2-({6-[4-(4-tert-butylbenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4-2.74 501 yl}amino)ethyl]acetamideN-[2-({6-[4-(1-adamantylcarbonyl)piperazin-1-yl]-2-phenylpyrimidin-4-2.76 503 yl}amino)ethyl]acetamideN-[2-({6-[4-(4-methoxybenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.43475 yl}amino)ethyl]acetamideN-[2-({6-[4-(4-cyclohexylbenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4-2.96 527 yl}amino)ethyl]acetamideN-[2-({6-[4-(1-naphthoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.59 495yl}amino)ethyl]acetamideN-[2-({6-[4-(4-bromo-3-methylbenzoyl)piperazin-1-yl]-2- 2.68 539phenylpyrimidin-4-yl}amino)ethyl]acetamideN-[2-({6-[4-(5-chloro-2-hydroxybenzoyl)piperazin-1-yl]-2- 2.48 495phenylpyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(6-{4-[4-(dimethylamino)benzoyl]piperazin-1-yl}-2- 2.44 488phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(acetylamino)acetyl]piperazin-1-yl}-2-phenylpyrimidin-4-2.41 440 yl)amino]ethyl}acetamideN-{2-[(6-{4-[(4-hydroxy-3-methoxyphenyl)acetyl]piperazin-1-yl}-2- 2.30505 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-[2-({6-[4-(3-hydroxy-4-methylbenzoyl)piperazin-1-yl]-2- 2.41 475phenylpyrimidin-4-yl}amino)ethyl]acetamideN-[2-({6-[4-(4-fluoro-1-naphthoyl)piperazin-1-yl]-2-phenylpyrimidin-4-2.65 513 yl}amino)ethyl]acetamideN-[2-({6-[4-(5-formyl-2-hydroxybenzoyl)piperazin-1-yl]-2- 2.37 489phenylpyrimidin-4-yl}amino)ethyl]acetamideN-[2-({6-[4-(cyclohex-1-en-1-ylcarbonyl)piperazin-1-yl]-2- 2.46 449phenylpyrimidin-4-yl}amino)ethyl]acetamideN-[2-({6-[4-([1,1′-biphenyl]-4-ylcarbonyl)piperazin-1-yl]-2- 2.74 521phenylpyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(6-{4-[(4-bromophenyl)acetyl]piperazin-1-yl}-2-phenylpyrimidin-4-2.60 537 yl)amino]ethyl}acetamideN-{2-[(6-{4-[2-(methylsulfanyl)benzoyl]piperazin-1-yl}-2- 2.48 491phenylpyrimidin-4-yl)amino]ethyl}acetamideN-[2-({6-[4-(4-benzoylbenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.63550 yl}amino)ethyl]acetamideN-{2-[(2-phenyl-6-{4-[4-(trifluoromethyl)benzoyl]piperazin-1- 2.63 513yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({6-[4-(4-acetylbenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.36487 yl}amino)ethyl]acetamideN-[2-({6-[4-(4-cyanobenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.59470 yl}amino)ethyl]acetamideN-{2-[(2-phenyl-6-{4-[3-(trifluoromethyl)benzoyl]piperazin-1- 2.60 513yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({6-[4-(3-cyanobenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.37470 yl}amino)ethyl]acetamideN-[2-({6-[4-(diphenylacetyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.70535 yl}amino)ethyl]acetamideN-[2-({6-[4-(4-ethylbenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.57473 yl}amino)ethyl]acetamideN-[2-({6-[4-(2-hydroxybenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.30461 yl}amino)ethyl]acetamideN-[2-({6-[4-(3-bromobenzoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.54525 yl}amino)ethyl]acetamideN-(2-{[6-(4-{[(4-chlorophenyl)sulfanyl]acetyl}piperazin-1-yl)-2- 2.68525 phenylpyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(6-{4-[(4-acetyl-3,5-dimethyl-1H-pyrrol-2-yl)carbonyl]piperazin-1-2.34 504 yl}-2-phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-phenyl-6-{4-[(2E)-3-thien-3-ylprop-2-enoyl]piperazin-1- 2.51477 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[2-furyl(morpholin-4-yl)acetyl]piperazin-1-yl}-2- 2.02 534phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(2-methyl-1H-benzimidazol-5-yl)carbonyl]piperazin-1-yl}-2-2.40 499 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-(4-isobutyrylpiperazin-1-yl)-2-phenylpyrimidin-4- 2.27 411yl]amino}ethyl)acetamideN-{2-[(6-{4-[(1H-benzimidazol-2-ylsulfanyl)acetyl]piperazin-1-yl}-2-2.27 531 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(2-hydroxyquinolin-4-yl)carbonyl]piperazin-1-yl}-2- 2.30512 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(5-chlorothien-2-yl)carbonyl]piperazin-1-yl}-2- 2.54 485phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(2E)-3-(3-cyanophenyl)prop-2-enoyl]piperazin-1-yl}-2- 2.53496 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(5-nitrothien-3-yl)carbonyl]piperazin-1-yl}-2- 2.41 496phenylpyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-(4-{[5-(methylsulfonyl)thien-2-yl]carbonyl}piperazin-1-yl)-2-2.33 529 phenylpyrimidin-4-yl]amino}ethyl)acetamideN-(2-{[2-phenyl-6-(4-{[4-(trifluoromethyl)cyclohexyl]carbonyl}piperazin-2.64 519 1-yl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(6-{4-[(3-ethoxythien-2-yl)carbonyl]piperazin-1-yl}-2- 2.60 495phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(2E)-3-(2-furyl)prop-2-enoyl]piperazin-1-yl}-2- 2.45 461phenylpyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-phenyl-6-[4-(2,3,5,6-tetrafluoro-4-methylbenzoyl)piperazin-1-2.68 531 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({6-[4-(5-bromo-2-furoyl)piperazin-1-yl]-2-phenylpyrimidin-4- 2.46515 yl}amino)ethyl]acetamideN-[2-({2-phenyl-6-[4-(4,4,4-trifluoro-3-hydroxy-3- 2.38 495methylbutanoyl)piperazin-1-yl]pyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(2-phenyl-6-{4-[(2E)-3-(2,3,4-trifluorophenyl)prop-2- 2.66 525enoyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(8-hydroxyquinolin-2-yl)carbonyl]piperazin-1-yl}-2- 2.49512 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-[2-({6-[4-(6-hydroxy-2-naphthoyl)piperazin-1-yl]-2-phenylpyrimidin-4-2.41 511 yl}amino)ethyl]acetamideN-{2-[(6-{4-[(2E)-3-(4-isopropylphenyl)prop-2-enoyl]piperazin-1-yl}-2-2.80 513 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-phenyl-6-{4-[(2E)-3-thien-2-ylprop-2-enoyl]piperazin-1- 2.49477 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-phenyl-6-{4-[(3E)-4-phenylbut-3-enoyl]piperazin-1-yl}pyrimidin-2.58 485 4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(1-benzoylpiperidin-4-yl)carbonyl]piperazin-1-yl}-2- 2.39556 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-(4-{4-[(aminocarbothioyl)amino]benzoyl}piperazin-1-yl)-2- 2.46519 phenylpyrimidin-4-yl]amino}ethyl)acetamide methyl3-{[4-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.21 504yl)piperazin-1-yl]carbonyl}isonicotinateN-[2-({6-[4-(2-oxo-3-phenylpropanoyl)piperazin-1-yl]-2-phenylpyrimidin-2.58 487 4-yl}amino)ethyl]acetamideN-{2-[(6-{4-[5-(1,2-dithiolan-3-yl)pentanoyl]piperazin-1-yl}-2- 2.75 529phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(2-methyl-5,6-dihydro-1,4-oxathiin-3-yl)carbonyl]piperazin-2.33 483 1-yl}-2-phenylpyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-phenyl-6-[4-(1H-tetraazol-1-ylacetyl)piperazin-1-yl]pyrimidin-4-2.39 451 yl}amino)ethyl]acetamideN-{2-[(6-{4-[3-(2-furyl)propanoyl]piperazin-1-yl}-2-phenylpyrimidin-4-2.45 465 yl)amino]ethyl}acetamideN-{2-[(2-phenyl-6-{4-[(2E,4E)-5-phenylpenta-2,4-dienoyl]piperazin-1-2.69 497 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-(4-{[2-(4-methylphenoxy)pyridin-3-yl]carbonyl}piperazin-1-yl)-2.57 552 2-phenylpyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-phenyl-6-{4-[(2E)-3-pyridin-2-ylprop-2-enoyl]piperazin-1- 2.23472 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({6-[4-(3-methyl-2-nitrobenzoyl)piperazin-1-yl]-2-phenylpyrimidin-2.51 504 4-yl}amino)ethyl]acetamideN-[2-({2-phenyl-6-[4-(3-thien-2-ylpropanoyl)piperazin-1-yl]pyrimidin-4-2.49 479 yl}amino)ethyl]acetamideN-{2-[(6-{4-[(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- 2.46 507yl)acetyl]piperazin-1-yl}-2-phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{4-[(4′-hydroxy[1,1′-biphenyl]-4-yl)carbonyl]piperazin-1-yl}-2-2.50 537 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-[2-({6-[4-(cyclohex-3-en-1-ylcarbonyl)piperazin-1-yl]-2- 2.58 449phenylpyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(6-{4-[3-(4-hydroxyphenyl)propanoyl]piperazin-1-yl}-2- 2.30 489phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-phenyl-6-{4-[(2E)-3-phenylprop-2-enoyl]piperazin-1- 2.53 471yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-phenyl-6-{4-[3-(3,4,5-trimethoxyphenyl)propanoyl]piperazin-1-2.40 563 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-(4-acetylpiperazin-1-yl)-2-phenylpyrimidin-4- 2.44 383yl]amino}ethyl)acetamideN-(2-{[2-phenyl-6-(4-propionylpiperazin-1-yl)pyrimidin-4- 2.19 397yl]amino}ethyl)acetamideN-{2-[(6-{4-[2-hydroxy-5-(1H-pyrrol-1-yl)benzoyl]piperazin-1-yl}-2- 2.56526 phenylpyrimidin-4-yl)amino]ethyl}acetamide

EXAMPLE 8

Synthesis of Compounds 34.1-34.155

2-(4-Chlorophenyl)pyrimidine-4,6-diol (30)

To sodium ethoxide (48 ml of a 21% wt solution in ethanol diluted with afurther 130 ml ethanol) was added 4-chlorobenzamidine (8 g) and diethylmalonate (6.67 ml) and the solution left to stir at 40° C. for 96 hrs.The reaction mixture was subsequently cooled to 5° C. and acidifiedcautiously to pH 2 using concentrated hydrochloric acid. The solid thusprecipitated was filtered, washed with excess cold water, then 50 mldiethyl ether and dried in vacuo yielding the title compound (7.51 g).

δ_(H) (d⁶-DMSO): 5.36 (1H, s), 7.53-7.58 (2H, d), 8.05-8.10 (2H, d); m/z(ES⁺) 223 (MH)⁺

4,6-Dichloro-2-(4-chlorophenyl)pyrimidine (31)

To 2-(4-chlorophenyl)pyrimidine-4,6-diol (6.43 g) in phosphorousoxychloride (50 ml) was added N,N-dimethylformamide (10 drops) and themixture heated to reflux for 16 hrs. After this time, the phosphorousoxychloride was removed in vacuo yielding a crude sample of the titlecompound. Cold water was cautiously added to remove traces ofphosphorous oxychloride, then the solid filtered and dried in vacuo(6.81 g).

δ_(H) (d⁶-DMSO): 7.68-7.72 (2H, d), 8.05 (1H, s), 8.36-8.40 (2H, d); m/z(ES⁺) 258 (MH)⁺

N-(2-{[6-Chloro-2-(4-chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamide(32)

N-Acetylethylenediamine (1.02 g) was dissolved in ethanol (250 ml) and4,6-dichloro-2-(4-chlorophenyl)pyrimidine (2.5 g) then triethylamine(1.35 ml) added. The mixture was heated to 85° C. with stirring for 48hrs. The solvent was then removed in vacuo and purified by columnchromatography on silica gel eluting first with ethyl acetate then amixture of ethyl acetate and methanol (9:1 v/v) to furnish the titlecompound (1.29 g).

δ_(H) (CDCl₃): 1.95 (3H, s), 3.51-3.56 (2H, m), 3.56-3.67 (2H, br s),5.70-5.75 (1H, br s), 5.95-6.02 (1H, br s), 6.30 (1H, s), 7.38-7.42 (2H,d), 8.28-8.33 (2H, d)

N-(2-{[2-(4-Chlorophenyl)-6-piperazin-1-ylpyrimidin-4-yl]amino}ethyl)acetamide(33)

N-(2-{[6-Chloro-2-(4-chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamide(1.00 g) and piperazine (2.66 g) were dissolved in DMSO (40 ml) andsodium hydrogencarbonate added (1.29 g). The mixture was heated to 110°C. for 6 hrs. The solvent was removed in vacuo and the residuepartitioned between ethyl acetate (100 ml) and water (100 ml). Theaqueous phase was washed further with ethyl acetate (2×100 ml) and thecombined organics subsequently washed with saturated brine solution (50ml), dried over magnesium sulphate, filtered and the solvent removed invacuo to afford the title compound (1.18 g).

δ_(H) (CDCl₃): 1.86 (3H, s), 2.93-2.98 (4H, m), 3.43-3.50 (2H, m),3.55-3.64 (6H, m), 4.92-4.95 (1H, m), 5.43 (1H, s), 6.52-6.59 (1H, brs), 7.37-7.40 (2H, d), 8.28-8.32 (2H, d)

Library Compound:

N-[2-({2-(4-Chlorophenyl)-6-[4-(quinolin-2-ylcarbonyl)piperazin-1-yl]pyrimidin-4-yl}amino)ethyl]acetamide(34.1)

A solution of quinaldic acid (60 μl of a 0.3M solution in NMP), HATU (60μl of a 0.3M solution in NMP) and diisopropylethylamine (60 μl of a 0.3Msolution in NMP) was shaken at ambient temperature in a well of a 96position microtitre plate for 5 min.N-(2-{[2-(4-chlorophenyl)-6-piperazin-1-ylpyrimidin-4-yl]amino}ethyl)acetamide(30 μl of a 0.3M solution in NMP) was then added and the mixture shakenfor a further 12 hr. Purification via ion exchange silica (SCX) yieldsthe title compound.

LCMS (Method A) RT=2.80 min; m/z (ES⁺) 530 (MH)⁺

The following compounds 34.2-34.155 were synthesised in an analogousmanner: Mass Ion Retention (ES⁺) Name Time (min) (MH)⁺N-[2-({2-(4-chlorophenyl)-6-[4-(isoquinolin-3-ylcarbonyl)piperazin-1-2.75 530 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(quinoxalin-2-ylcarbonyl)piperazin-1-2.75 531 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(isoquinolin-1-ylcarbonyl)piperazin-1-2.74 530 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(2-hydroxy-5-nitrobenzoyl)piperazin-1-2.71 540 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(2,5-dihydroxybenzoyl)piperazin-1- 2.54511 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(pyrazin-2-ylcarbonyl)piperazin-1- 2.49481 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(pyridin-3-ylcarbonyl)piperazin-1- 2.44480 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-(2-{[2-(4-chlorophenyl)-6-(4-isonicotinoylpiperazin-1-yl)pyrimidin-4-2.38 480 yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2-hydroxypyridin-3- 2.37 496yl)carbonyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(1H-indol-2-ylcarbonyl)piperazin-1- 2.92518 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(1H-indol-3-ylcarbonyl)piperazin-1- 2.73518 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(3-nitrobenzoyl)piperazin-1-yl]pyrimidin-2.79 524 4-yl}amino)ethyl]acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(1-methyl-6-oxo-1,4,5,6- 2.45 514tetrahydropyridazin-3-yl)carbonyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[1-(2,7-dimethylpyrazolo[1,5-a]pyrimidin-2.65 548 6-yl)vinyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(3-hydroxy-4- 2.59 539methoxyphenyl)acetyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2E)-3-(3-nitrophenyl)prop-2- 2.91 550enoyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-{4-[3-(1H-benzimidazol-2-yl)propanoyl]piperazin-1-yl}-2-(4-2.30 547 chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(2-hydroxy-4-methylbenzoyl)piperazin-1-2.70 509 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(2-hydroxy-3-methoxybenzoyl)piperazin-2.62 525 1-yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(2-hydroxy-3-methylbenzoyl)piperazin-1-2.79 509 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(1H-indol-3-ylacetyl)piperazin-1- 2.73532 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[3-(1H-indol-3-yl)propanoyl]piperazin-1-2.80 546 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(pyridin-2-ylcarbonyl)piperazin-1- 2.53480 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[4-(1H-indol-3-yl)butanoyl]piperazin-1-2.91 560 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(5-methylpyrazin-2- 2.54 495yl)carbonyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-3.07 560 yl)carbonyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(4-oxo-4,5,6,7-tetrahydro-1-benzofuran-2.61 5373-yl)carbonyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[2-(4-chlorophenyl)-6-(4-{[2-(methylsulfanyl)pyridin-3- 2.72 526yl]carbonyl}piperazin-1-yl)pyrimidin-4-yl]amino}ethyl)acetamideN-(2-{[6-{4-[(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)carbonyl]piperazin-1-2.81 539 yl}-2-(4-chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2Z)-2-(3-oxo-2-benzofuran-1(3H)- 2.59546 ylidene)ethanoyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-[4-(1-benzothien-2-ylcarbonyl)piperazin-1-yl]-2-(4- 3.01 535chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[4-(trifluoromethoxy)benzoyl]piperazin-1-3.01 563 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-{4-[(5-chloro-2-hydroxypyridin-3-yl)carbonyl]piperazin-1-yl}-2-2.51 530 (4-chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2E)-4-oxo-4-(2,3,4,5,6- 3.24 603pentamethylphenyl)but-2-enoyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[4-(trifluoroacetyl)benzoyl]piperazin-1-2.69 575 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{4-[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.75 570 yl]piperazin-1-yl}-2-oxoethyl)-4-chlorobenzamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2,4-dihydroxypyrimidin-5- 2.31 513yl)carbonyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(1,2,3-thiadiazol-4-ylcarbonyl)piperazin-2.58 487 1-yl]pyrimidin-4-yl}amino)ethyl]acetamideN-(2-{[6-(4-{[5-chloro-2-(methylsulfanyl)pyrimidin-4- 2.85 561yl]carbonyl}piperazin-1-yl)-2-(4-chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-(2-{[2-(4-chlorophenyl)-6-(4-{[1-(2-furylmethyl)-5-oxopyrrolidin-3-2.61 566 yl]carbonyl}piperazin-1-yl)pyrimidin-4-yl]amino}ethyl)acetamideN-(2-{[6-{4-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]piperazin-1-2.91 539 yl}-2-(4-chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(4-nitrophenyl)acetyl]piperazin-1- 2.82538 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2,5-dimethoxyphenyl)acetyl]piperazin-2.82 553 1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(3-methoxyphenyl)acetyl]piperazin-1-2.78 523 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(4-methoxyphenyl)acetyl]piperazin-1-2.77 523 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2-methoxyphennyl)acetyl]piperazin-1-2.81 523 yl}pyrmidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(1,2,3,4-tetrahydronaphthalen-2- 3.04 533ylcarbonyl)piperazin-1-yl]pyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2R)-2-hydroxy-3- 2.75 523phenylpropanoyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1- 2.68468 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(4-vinylbenzoyl)piperazin-1-yl]pyrimidin-2.93 505 4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(cyclohexylacetyl)piperazin-1- 2.98 499yl]pyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[4-(1H-pyrrol-1-yl)benzoyl]piperazin-1-2.98 544 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-2.78 576yl)propanoyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-[4-([1,1′-biphenyl]-4-ylacetyl)piperazin-1-yl]-2-(4- 3.09 569chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(6-methoxy-3-oxo-2,3-dihydro-1H-inden-2.75 577 1-yl)acetyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(3-nitrophenyl)acetyl]piperazin-1- 2.83538 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2-methylphenyl)acetyl]piperazin-1- 2.85507 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(4-methylphenyl)acetyl]piperazin-1- 2.89507 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(3-methylbenzoyl)piperazin-1- 2.86 493yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(4-methylbenzoyl)piperazin-1- 2.87 493yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(2-methylbenzoyl)piperazin-1- 2.85 493yl]pyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(3-methylphenyl)acetyl]piperazin-1- 2.88507 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-[4-(4-butylbenzoyl)piperazin-1-yl]-2-(4-chlorophenyl)pyrimidin-3.26 535 4-yl]amino}ethyl)acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(4-nitrobenzoyl)piperazin-1-yl]pyrimidin-2.83 524 4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(2-phenoxypropanoyl)piperazin-1- 2.86 523yl]pyrimidin-4-yl}amino)ethyl]acetamideN-(2-{[6-[4-(1,3-benzodioxol-5-ylcarbonyl)piperazin-1-yl]-2-(4- 2.73 523chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(phenylacetyl)piperazin-1-yl]pyrimidin-4-2.84 493 yl}amino)ethyl]acetamideN-(2-{[6-[4-(bicyclo[2.2.1]hept-5-en-2-ylcarbonyl)piperazin-1-yl]-2-(4-2.80 495 chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[hydroxy(phenyl)acetyl]piperazin-1- 2.68509 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2-naphthyloxy)acetyl]piperazin-1- 3.02559 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(1-phenylcyclopentyl)carbonyl]piperazin-3.12 547 1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(2-sulfanylbenzoyl)piperazin-1- 2.99 511yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-2.51 473 1-yl]pyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[cyclopentyl(phenyl)acetyl]piperazin-1-3.24 561 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-[4-(4-tert-butylbenzoyl)piperazin-1-yl]-2-(4- 3.16 535chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-(2-{[6-[4-(1-adamantylcarbonyl)piperazin-1-yl]-2-(4- 3.17 537chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(4-methoxybenzoyl)piperazin-1- 2.77 509yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(4-cyclohexylbenzoyl)piperazin-1- 3.37561 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(1-naphthoyl)piperazin-1-yl]pyrimidin-4-2.97 529 yl}amino)ethyl]acetamideN-(2-{[6-(4-benzoylpiperazin-1-yl)-2-(4-chlorophenyl)pyrimidin-4- 2.73479 yl]amino}ethyl)acetamide N-{2-[(2-(4-chlorophenyl)-6-{4-[3-(2,4-2.56 539 dihydroxyphenyl)propanoyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-[4-(4-bromo-3-methylbenzoyl)piperazin-1-yl]-2-(4- 3.06 573chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-(2-{[6-[4-(5-chloro-2-hydroxybenzoyl)piperazin-1-yl]-2-(4- 2.78 529chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[4-(dimethylamino)benzoyl]piperazin-1-2.78 522 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-{4-[(acetylamino)acetyl]piperazin-1-yl}-2-(4- 2.37 474chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(4-hydroxy-3- 2.59 539methoxyphenyl)acetyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(3-hydroxy-4-methylbenzoyl)piperazin-1-2.75 509 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(3-phenylprop-2-ynoyl)piperazin-1- 2.96503 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(4-fluoro-1-naphthoyl)piperazin-1- 3.01547 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(5-formyl-2-hydroxybenzoyl)piperazin-1-2.55 523 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(cyclohex-1-en-1-ylcarbonyl)piperazin-1-2.78 483 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-(2-{[6-[4-([1,1′-biphenyl]-4-ylcarbonyl)piperazin-1-yl]-2-(4- 3.09 555chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-(2-{[6-{4-[(4-bromophenyl)acetyl]piperazin-1-yl}-2-(4- 2.93 573chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[2-(methylsulfanyl)benzoyl]piperazin-1-2.81 525 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[4-(methylsulfonyl)benzoyl]piperazin-1-2.62 557 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-[4-(4-benzoylbenzoyl)piperazin-1-yl]-2-(4- 3.00 583chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[4-(trifluoromethyl)benzoyl]piperazin-1-3.00 547 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-[4-(4-acetylbenzoyl)piperazin-1-yl]-2-(4-chlorophenyl)pyrimidin-2.70 521 4-yl]amino}ethyl)acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(4-cyanobenzoyl)piperazin-1-yl]pyrimidin-2.73 504 4-yl}amino)ethyl]acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[3-(trifluoromethyl)benzoyl]piperazin-1-2.98 547 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(3-cyanobenzoyl)piperazin-1-yl]pyrimidin-2.76 504 4-yl}amino)ethyl]acetamideN-(2-{[6-[4-(1H-benzimidazol-5-ylcarbonyl)piperazin-1-yl]-2-(4- 2.26 519chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(diphenylacetyl)piperazin-1-yl]pyrimidin-3.11 569 4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(4-ethylbenzoyl)piperazin-1-yl]pyrimidin-3.00 507 4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(2-hydroxybenzoyl)piperazin-1- 2.62 495yl]pyrimidin-4-yl}amino)ethyl]acetamideN-(2-{[6-[4-(3-bromobenzoyl)piperazin-1-yl]-2-(4- 2.93 559chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(4-oxopentanoyl)piperazin-1-yl]pyrimidin-2.47 473 4-yl}amino)ethyl]acetamide N-(2-{[2-(4-chlorophenyl)-6-(4-{[(4-3.05 559 chlorophenyl)sulfanyl]acetyl}piperazin-1-yl)pyrimidin-4-yl]amino}ethyl)acetamideN-(2-{[6-{4-[(4-acetyl-3,5-dimethyl-1H-pyrrol-2-yl)carbonyl]piperazin-1-2.62 538 yl}-2-(4-chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2E)-3-thien-3-ylprop-2-enoyl]piperazin-2.81 511 1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[2-furyl(4-phenylpiperazin-1- 2.60 643yl)acetyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[2-furyl(morpholin-4-yl)acetyl]piperazin-1-2.31 568 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2-methyl-1H-benzimidazol-5- 2.26 533yl)carbonyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[2-(4-chlorophenyl)-6-(4-isobutyrylpiperazin-1-yl)pyrimidin-4-2.61 445 yl]amino}ethyl)acetamideN-(2-{[6-{4-[(1H-benzimidazol-2-ylsulfanyl)acetyl]piperazin-1-yl}-2-(4-2.54 565 chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2-hydroxyquinolin-4- 2.61 546yl)carbonyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(5-chlorothien-2-yl)carbonyl]piperazin-1-2.92 519 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2E)-3-(3-cyanophenyl)prop-2- 2.88 530enoyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(5-nitrothien-3-yl)carbonyl]piperazin-1-2.79 530 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[2-(4-chlorophenyl)-6-(4-{[4- 2.97 553(trifluoromethyl)cyclohexyl]carbonyl}piperazin-1-yl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(3-ethoxythien-2-yl)carbonyl]piperazin-1-2.78 529 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2E)-3-(2-furyl)prop-2-enoyl]piperazin-1-2.74 495 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(2,3,5,6-tetrafluoro-4- 3.11 565methylbenzoyl)piperazin-1-yl]pyrimidin-4-yl}amino)ethyl]acetamideN-(2-{[6-[4-(5-bromo-2-furoyl)piperazin-1-yl]-2-(4- 2.85 549chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(4,4,4-trifluoro-3-hydroxy-3- 2.72 529methylbutanoyl)piperazin-1-yl]pyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2E)-3-(2,3,4-trifluorophenyl)prop-2-3.04 559 enoyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(8-hydroxyquinolin-2- 2.82 546yl)carbonyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(6-hydroxy-2-naphthoyl)piperazin-1- 2.73545 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2E)-3-(4-isopropylphenyl)prop-2- 3.20547 enoyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2E)-3-thien-2-ylprop-2-enoyl]piperazin-2.85 511 1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(3E)-4-phenylbut-3-enoyl]piperazin-1-2.92 519 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-{4-[(1-benzoylpiperidin-4-yl)carbonyl]piperazin-1-yl}-2-(4-2.73 590 chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-(2-{[6-(4-{4-[(aminocarbothioyl)amino]benzoyl}piperazin-1-yl)-2-(4-2.52 553 chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamide methyl3-({4-[6-{[2-(acetylamino)ethyl]amino}-2-(4- 2.57 538chlorophenyl)pyrimidin-4-yl]piperazin-1-yl}carbonyl)isonicotinateN-[2-({2-(4-chlorophenyl)-6-[4-(2-oxo-3-phenylpropanoyl)piperazin-1-2.94 521 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[5-(1,2-dithiolan-3-yl)pentanoyl]piperazin-2.96 563 1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2-methyl-5,6-dihydro-1,4-oxathiin-3-2.67 517 yl)carbonyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(1H-tetraazol-1-ylacetyl)piperazin-1-2.43 485 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[3-(2-furyl)propanoyl]piperazin-1- 2.75497 yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2E,4E)-5-phenylpenta-2,4- 3.00 531dienoyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(3-nitropropanoyl)piperazin-1- 2.56 476yl]pyrimidin-4-yl}amino)ethyl]acetamideN-(2-{[2-(4-chlorophenyl)-6-(4-{[2-(4-methylphenoxy)pyridin-3- 2.97 586yl]carbonyl}piperazin-1-yl)pyrimidin-4-yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(2E)-3-pyridin-2-ylprop-2- 2.51 506enoyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(3-methyl-2-nitrobenzoyl)piperazin-1-2.87 538 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(3-thien-2-ylpropanoyl)piperazin-1- 2.82513 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(5-methyl-2,4-dioxo-3,4- 2.41 541dihydropyrimidin-1(2H)-yl)acetyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[(4′-hydroxy[1,1′-biphenyl]-4- 2.82 571yl)carbonyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(cyclohex-3-en-1-ylcarbonyl)piperazin-1-2.81 483 yl]pyrimidin-4-yl}amino)ethyl]acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[3-(4-hydroxyphenyl)propanoyl]piperazin-2.60 523 1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[3-(3,4,5- 2.71 597trimethoxyphenyl)propanoyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-(2-{[6-(4-acetylpiperazin-1-yl)-2-(4-chlorophenyl)pyrimidin-4- 2.45417 yl]amino}ethyl)acetamideN-(2-{[2-(4-chlorophenyl)-6-(4-propionylpiperazin-1-yl)pyrimidin-4- 2.52431 yl]amino}ethyl)acetamideN-{2-[(2-(4-chlorophenyl)-6-{4-[2-hydroxy-5-(1H-pyrrol-1- 2.86 560yl)benzoyl]piperazin-1-yl}pyrimidin-4-yl)amino]ethyl}acetamideN-[2-({2-(4-chlorophenyl)-6-[4-(2-hydroxy-3-nitrobenzoyl)piperazin-1-2.76 540 yl]pyrimidin-4-yl}amino)ethyl]acetamide

EXAMPLE 9

Synthesis of Compounds 36.1-36.141

N-[2-({6-[(2-Aminoethyl)amino]-2-phenylpyrimidin-4-yl}amino)ethyl]acetamide(35)

N-{2-[(6-Chloro-2-phenylpyrimidin-4-yl)amino]ethyl}acetamide (100 mg)was dissolved in ethylenediamine (5 ml) and the stirred under reflux for4 hrs. The reaction mixture was then cooled to ambient temperature andthe solvent removed in vacuo. Purification via flash chromatography onsilica gel eluting first with a mixture of ethyl acetate and methanol(9:1 v/v) then a mixture of ethyl acetate, methanol and ammoniumhydroxide (80:20:2 v/v/v) to furnish the title compound (89 mg).

δ_(H) (d⁶-DMSO): 1.80 (3H, s), 2.63-2.70 (2H, t), 3.18-3.36 (6H, m),5.35 (1H, s), 6.50-6.61 (2H, m), 7.38-7.40 (3H, m), 7.90-7.95 (1H, m),8.22-8.25 (2H, m); m/z (ES⁺) 315 (MH)⁺

Library Example:

N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino]ethyl}quinoline-2-carboxamide(36.1)

A solution of quinaldic acid (30 μl of a 0.3M solution in NMP), HATU (30μl of a 0.3M solution in NMP) and diisopropylethylamine (30 μl of a 0.3Msolution in NMP) was shaken at ambient temperature in a well of a 96position microtitre plate for 2 hrs.N-[2-({6-[(2-aminoethyl)amino]-2-phenylpyrimidin-4-yl}amino)ethyl]acetamide(30 μl of a 0.3M solution in NMP) was then added and the mixture shakenfor a further 12 hrs. Purification via ion exchange silica (SCX) yieldsthe title compound.

LCMS (Method A) RT=2.67 min; m/z (ES⁺) 470 (MH)⁺

The following compounds 36.2-36.141 were synthesized in an analogousmanner: Mass ion Retention (ES⁺) Name Time (min) (MH)⁺N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.67 470yl)amino]ethyl}isoquinoline-3-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.58 470yl)amino]ethyl}isoquinoline-1-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.74 458yl)amino]ethyl}indoline-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.41 421yl)amino]ethyl}pyrazine-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.32 420yl)amino]ethyl}nicotinamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.31 420yl)amino]ethyl}isonicotinamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.38 436yl)amino]ethyl}-2-hydroxynicotinamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.68 458yl)amino]ethyl}-1H-indole-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.58 458yl)amino]ethyl}-1H-indole-3-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.43 479yl)amino]ethyl}-2-(3-hydroxy-4-methoxyphenyl)acetamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.67484 yl)amino]ethyl}-3-(1H-indol-3-yl)prop-2-enamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.71490 yl)amino]ethyl}-3-(3-nitrophenyl)prop-2-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.27 487yl)amino]ethyl}-3-(1H-benzimidazol-2-yl)propanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.73 449yl)amino]ethyl}-2-hydroxy-4-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.59 465yl)amino]ethyl}-2-hydroxy-3-methoxybenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.80 449yl)amino]ethyl}-2-hydroxy-3-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.53 472yl)amino]ethyl}-2-(1H-indol-3-yl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.64 486yl)amino]ethyl}-3-(1H-indol-3-yl)propanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.48 420yl)amino]ethyl}pyridine-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.69 500yl)amino]ethyl}-4-(1H-indol-3-yl)butanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.45 435yl)amino]ethyl}-5-methylpyrazine-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.81 500yl)amino]ethyl}-5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.54 477yl)amino]ethyl}-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.48 466yl)amino]ethyl}-2-(methylsulfanyl)nicotinamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.59 479yl)amino]ethyl}-1-tert-butyl-3-methyl-1H-pyrazole-5-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.75 475yl)amino]ethyl}-1-benzothiophene-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.80 503yl)amino]ethyl}-4-(trifluoromethoxy)benzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.51 470yl)amino]ethyl}-5-chloro-2-hydroxynicotinamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.56 515yl)amino]ethyl}-4-(trifluoroacetyl)benzamideN-[2-({2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.65 510yl)amino]ethyl}amino)-2-oxoethyl]-4-chlorobenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.44 427yl)amino]ethyl}-1,2,3-thiadiazole-4-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.65 501yl)amino]ethyl}-5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.53 506yl)amino]ethyl}-1-(2-furylmethyl)-5-oxopyrrolidine-3-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.66 479yl)amino]ethyl}-3-tert-butyl-1-methyl-1H-pyrazole-5-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.59 493yl)amino]ethyl}-2-(2,5-dimethoxyphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.55 463yl)amino]ethyl}-2-(3-methoxyphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.54 463yl)amino]ethyl}-2-(4-methoxyphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.59 463yl)amino]ethyl}-2-(2-methoxyphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.74 473yl)amino]ethyl}-1,2,3,4-tetrahydronaphthalene-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.59 463yl)amino]ethyl}-2-hydroxy-3-phenylpropanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.45 408yl)amino]ethyl}-1H-pyrrole-2-carboxamide(3S,4R,5S)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-2.15 471 yl)amino]ethyl}-3,4,5-trihydroxycyclohex-1-ene-1-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.67 439yl)amino]ethyl}-2-cyclohexylacetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.76 484yl)amino]ethyl}-4-(1H-pyrrol-1-yl)benzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.45 488yl)amino]ethyl}-2-(4-oxo-2-thioxo-1,3-thiazolidin-3-yl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.86 509yl)amino]ethyl}-2-[1,1′-biphenyl]-4-ylacetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.56 517yl)amino]ethyl}-2-(6-methoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.61 447yl)amino]ethyl}-2-(2-methylphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.61 447yl)amino]ethyl}-2-(4-methylphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.62 433yl)amino]ethyl}-3-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.62 433yl)amino]ethyl}-4-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.56 433yl)amino]ethyl}-2-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.62 447yl)amino]ethyl}-2-(3-methylphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.67 463yl)amino]ethyl}-2-phenoxypropanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.55 463yl)amino]ethyl}-1,3-benzodioxole-5-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.54 433yl)amino]ethyl}-2-phenylacetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.61 435yl)amino]ethyl}bicyclo[2.2.1]hept-5-ene-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.46 449yl)amino]ethyl}-2-hydroxy-2-phenylacetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.78 487yl)amino]ethyl}-1-phenylcyclopentanecarboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.58 449yl)amino]ethyl}-2-sulfanylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.37 413yl)amino]ethyl}tetrahydrofuran-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.85 501yl)amino]ethyl}-2-cyclopentyl-2-phenylacetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.87 475yl)amino]ethyl}-4-tert-butylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.79 477yl)amino]ethyl}adamantane-1-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.57 449yl)amino]ethyl}-4-methoxybenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 3.04 501yl)amino]ethyl}-4-cyclohexylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.66 469yl)amino]ethyl}-1-naphthamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.55 419yl)amino]ethyl}benzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.80 511yl)amino]ethyl}-4-bromo-3-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.77 469yl)amino]ethyl}-5-chloro-2-hydroxybenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.62 462yl)amino]ethyl}-4-(dimethylamino)benzamide2-(acetylamino)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-2.16 414 4yl)amino]ethyl}acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.40 479yl)amino]ethyl}-2-(4-hydroxy-3-methoxyphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.56 449yl)amino]ethyl}-3-hydroxy-4-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.70 443yl)amino]ethyl}-3-phenylprop-2-ynamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.72 487yl)amino]ethyl}-4-fluoro-1-naphthamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.64 463yl)amino]ethyl}-5-formyl-2-hydroxybenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.60 423yl)amino]ethyl}cyclohex-1-ene-1-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.71 513yl)amino]ethyl}-2-(4-bromophenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.57 465yl)amino]ethyl}-2-(methylsulfanyl)benzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.49 497yl)amino]ethyl}-4-(methylsulfonyl)benzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.81 523yl)amino]ethyl}-4-benzoylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.78 487yl)amino]ethyl}-4-(trifluoromethyl)benzamide4-acetyl-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-2.55 461 yl)amino]ethyl}benzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.60 444yl)amino]ethyl}-4-cyanobenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.76 487yl)amino]ethyl}-3-(trifluoromethyl)benzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.57 444yl)amino]ethyl}-3-cyanobenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.22 459yl)amino]ethyl}-1H-benzimidazole-5-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.83 509yl)amino]ethyl}-2,2-diphenylacetamide2-[({2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.53 477yl)amino]ethyl}amino)carbonyl]phenyl acetateN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.73 447yl)amino]ethyl}-4-ethylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.64 435yl)amino]ethyl}-2-hydroxybenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.71 499yl)amino]ethyl}-3-bromobenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.36 413yl)amino]ethyl}-4-oxopentanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.79 499yl)amino]ethyl}-2-[(4-chlorophenyl)sulfanyl]acetamide4-acetyl-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-2.51 478 yl)amino]ethyl}-3,5-dimethyl-1H-pyrrole-2-carboxamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.64451 yl)amino]ethyl}-3-thien-3-ylprop-2-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.64 583yl)amino]ethyl}-2-(2-furyl)-2-(4-phenylpiperazin-1-yl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.27 508yl)amino]ethyl}-2-(2-furyl)-2-morpholin-4-ylacetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.22 473yl)amino]ethyl}-2-methyl-1H-benzimidazole-5-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.41 385yl)amino]ethyl}-2-methylpropanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.50 505yl)amino]ethyl}-2-(1H-benzimidazol-2-ylsulfanyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.46 486yl)amino]ethyl}-2-hydroxyquinoline-4-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.70 459yl)amino]ethyl}-5-chlorothiophene-2-carboxamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.67470 yl)amino]ethyl}-3-(3-cyanophenyl)prop-2-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.64 470yl)amino]ethyl}-5-nitrothiophene-3-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenyylpyrimidin-4- 2.52 503yl)amino]ethyl}5-(methylsulfonyl)thiophene-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.74 493yl)amino]ethyl}-4-(trifluoromethyl)cyclohexanecarboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.62 469yl)amino]ethyl}-3-ethoxythiophene-2-carboxamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.59435 yl)amino]ethyl}-3-(2-furyl)prop-2-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.71 505yl)amino]ethyl}2,3,5,6-tetrafluoro-4-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.52 469yl)amino]ethyl}-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.81499 yl)amino]ethyl}-3-(2,3,4-trifluorophenyl)prop-2-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.71 486yl)amino]ethyl}-8-hydroxyquinoline-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.61 485yl)amino]ethyl}-6-hydroxy-2-naphthamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.96487 yl)amino]ethyl}-3-(4-isopropylphenyl)prop-2-enamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.64451 yl)amino]ethyl}-3-thien-2-ylprop-2-enamide(3E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.72459 yl)amino]ethyl}-4-phenylbut-3-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.57 530yl)amino]ethyl}-1-benzoylpiperidine-4-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.42 454yl)amino]ethyl}-4-nitro-1H-pyrazole-3-carboxamide methyl3-[({2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.45 478yl)amino]ethyl}amino)carbonyl]isonicotinateN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.74 503yl)amino]ethyl}-5-(1,2-dithiolan-3-yl)pentanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.51 457yl)amino]ethyl}-2-methyl-5,6-dihydro-1,4-oxathiine-3-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.55 437yl)amino]ethyl}-3-(2-furyl)propanamide(2E,4E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.82471 yl)amino]ethyl}-5-phenylpenta-2,4-dienamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.35 416yl)amino]ethyl}-3-nitropropanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.65 453yl)amino]ethyl}-2-oxo-2-thien-2-ylacetamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.40446 yl)amino]ethyl}-3-pyridin-2-ylprop-2-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.65 478yl)amino]ethyl}-3-methyl-2-nitrobenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.60 453yl)amino]ethyl}-3-thien-2-ylpropanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.29 481yl)amino]ethyl}-2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-2.65 511 yl)amino]ethyl}-4′-hydroxy[1,1′-biphenyl]-4-carboxamide(4R)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.32444 yl)amino]ethyl}-2-oxo-1,3-thiazolidine-4-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.58 423yl)amino]ethyl}cyclohex-3-ene-1-carboxamide ethyl(2E)-4-({2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.54441 yl)amino]ethyl}amino)-4-oxobut-2-enoateN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.41 463yl)amino]ethyl}-3-(4-hydroxyphenyl)propanamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.65445 yl)amino]ethyl}-3-phenylprop-2-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.31 357yl)amino]ethyl}acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.30 371yl)amino]ethyl}propanamideN-{2-[(6-{[2-(formylamino)ethyl]amino}-2-phenylpyrimidin-4- 2.73 480yl)amino]ethyl}acetamide

EXAMPLE 10

Synthesis of Compounds 41.1-41.144

5-Methyl-2-phenyl-pyrimidine-4,6-diol (37)

To ethanol (180 ml) was added sodium ethoxide solution (38 ml of a 21%wt solution in ethanol), benzamidine hydrochloride (5.0 g) anddiethylmethylmalonate (4.91 ml). The suspension was stirred at 40° C. inan inert atmosphere for 22 hrs after which time it was cooled to 5° C.(ice bath) and treated dropwise with concentrated hydrochloric acid to apH of 2.5. The resulting pink suspension was filtered and washed withexcess water. Purification by recrystallisation from boiling acetic acid(300 ml) afforded the title compound (4.22 g) after filtration andwashing with ethanol (20 ml) and diethyl ether (20 ml).

δ_(H) (d⁶-DMSO): 1.80 (3H, s), 7.45-7.55 (3H, m), 8.05-8.07 (2H, d); m/z(ES⁺) 203 (MH)⁺

4,6-Dichloro-5-methyl-2-phenylpyrimidine (38)

5-Methyl-2-phenylpyrimidine-4,6-diol (2.81 g) was added to a mixture ofphosphorous oxychloride (30 ml) and N,N-dimethylformamide (5 drops). Theresulting suspension became a solution on heating to reflux for 36 hrs.After this time the solvent was removed in vacuo. Iced water wascautiously added with stirring to reveal the title compound as a beigesolid (1.83 g) after filtration and washing with ethanol (20 ml) anddiethyl ether (20 ml).

δ_(H) (CDCl₃): 2.43-2.49 (3H, br s), 7.40-7.51 (3H, m), 8.33-8.40 (2H,m); m/z (ES⁺) 239 (MH)⁺

N-{2-[(6-Chloro-5-methyl-2-phenylpyrimidin-4-yl)amino]ethyl acetamide(39)

4,6-Dichloro-5-methyl-2-phenylpyrimidine (3.45 g),N-acetyethylenediamine (1.62 g) and N,N-diisopropylethylamine (2.05 g)were added to propan-2-ol (60 ml) with stirring. The resulting solutionwas heated to reflux for 46 hrs then cooled to 5° C. Precipitated saltimpurities were removed by filtration and the mother liquor evaporatedonto silica gel. Purification by column chromatography on silica geleluting with a mixture of ethyl acetate and methanol (9:1 v/v) furnishedthe title compound (3.28 g).

δ_(H) (d⁶-DMSO): 1.79 (3H, s), 2.11 (3H, s), 3.23-3.33 (2H, m),3.50-3.58 (2H, m), 7.23-7.28 (1H, m), 7.42-7.47 (3H, m), 7.92-8.00 (1H,m), 8.23-8.30 (2H, m); m/z (ES⁺) 305 (MH)⁺

N-[2-({6-[(2-Aminoethyl)amino]-5-methyl-2-phenylpyrimidin-4-yl}amino)ethyl]-acetamide(40)

N-{2-[(6-Chloro-5-methyl-2-phenylpyrimidin-4-yl)amino]ethyl}acetamide(2.0 g) was dissolved in ethylenediamine (40 ml) and heated withstirring to reflux for 21 hrs. After cooling to ambient temperature thesolution was evaporated onto silica gel (50 g). Purification via flashchromatography on silica gel eluting with a mixture of ethyl acetate,methanol and ammonium hydroxide (80:20:5 v/v/v) furnished the titlecompound (1.83 g).

δ_(H) (d6-DMSO): 1.78 (3H, s), 1.81 (3H, s), 2.50-2.53 (1H, t),2.70-2.75 (2H, t), 2.97-3.02 (1H, q), 3.23-3.29 (2H, m), 3.40-3.50 (2H,m), 6.00-6.04 (1H, m), 6.11-6.16 (1H, m), 7.07-7.25 (2H, m), 7.36-7.41(3H, m), 7.91-7.97 (1H, m), 8.28-8.33 (2H, m); m/z (ES⁺) 329 (MH)⁺

N-{2-[(6-([2-(Acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-yl)-amino]ethyl}benzamide(41.1)

Benzoic acid (55.8 mg), N,N-diisopropylethylamine (80 μl) and HATU (160mg) were stirred in NMP (685 μl) for 30 min. After this timeN-[2-({6-[(2-aminoethyl)amino]-5-methyl-2-phenylpyrimidin-4-yl}amino)ethyl]acetamide(150 mg) was added and the mixture stirred for 16 hrs at roomtemperature. Purification via SCX resin furnished the title compound (54mg).

δ_(H) (CDCl₃): 1.69 (3H, s), 1.80 (3H, s), 3.38-3.43 (2H, m), 3.60-3.73(4H, m), 3.83-3.90 (2H, m), 5.15-5.20 (2H, m), 6.90-6.95 (2H, t),7.18-7.22 (1H, t), 7.37-7.42 (2H, m), 7.42-7.48 (3H, m), 8.16-8.20 (1H,m), 8.30-8.37 (2H, m); m/z (ES⁺) 433 (MH)⁺

Library Example:

N-{2-[(6-{[2-(Acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-yl)amino]ethyl}quinoline-2-carboxamide(41.2)

A solution of quinaldic acid (30 μl of a 0.3M solution in NMP), HATU (30μl of a 0.3M solution in NMP) and diisopropylethylamine (30 μl of a 0.3Msolution in NMP) was shaken at ambient temperature in a well of a 96position microtitre plate for 45 min.N-[2-({6-[(2-aminoethyl)amino]-5-methyl-2-phenylpyrimidin-4-yl}amino)ethyl]acetamide(30 μl of a 0.3M solution in NMP) was then added and the mixture shakenfor a further 12 hrs. Purification via ion exchange silica (SCX) yieldsthe title compound.

LCMS (Method A) RT=2.67 min; m/z (ES⁺) 484 (MH)⁺

The following compounds 41.3-41.144 were synthesized in an analogousmanner: Mass Ion Retention (ES⁺) Name Time (min) (MH)⁺N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.57 484 yl)amino]ethyl}isoquinoline-3-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.50 485 yl)amino]ethyl}quinoxaline-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.57 484 yl)amino]ethyl}isoquinoline-1-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.30 435 yl)amino]ethyl}pyrazine-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.19 434 yl)amino]ethyl}nicotinamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.17 434 yl)amino]ethyl}isonicotinamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.23 450 yl)amino]ethyl}-2-hydroxynicotinamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.58 472 yl)amino]ethyl}-1H-indole-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.48 469 yl)amino]ethyl}-1H-indole-3-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.33 492 yl)amino]ethyl}-2-(3-hydroxy-4-methoxyphenyl)acetamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.58 498phenylpyrimidin-4-yl)amino]ethyl}-3-(1H-indol-3-yl)prop-2-enamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.64 504phenylpyrimidin-4-yl)amino]ethyl}-3-(3-nitrophenyl)prop-2-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.14 501 yl)amino]ethyl}-3-(1H-benzimidazol-2-yl)propanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.65 463 yl)amino]ethyl}-2-hydroxy-4-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.50 479 yl)amino]ethyl}-2-hydroxy-3-methoxybenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.75 463 yl)amino]ethyl}-2-hydroxy-3-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.42 486 yl)amino]ethyl}-2-(1H-indol-3-yl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.55 500 yl)amino]ethyl}-3-(1H-indol-3-yl)propanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.39 434 yl)amino]ethyl}pyridine-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.62 514 yl)amino]ethyl}-4-(1H-indol-3-yl)butanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.34 449 yl)amino]ethyl}-5-methylpyrazine-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.74 514yl)amino]ethyl}-5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.42 491yl)amino]ethyl}-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.44 480 yl)amino]ethyl}-2-(methylsulfanyl)nicotinamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.57 493 yl)amino]ethyl}-1-tert-butyl-3-methyl-1H-pyrazole-5-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.70 489 yl)amino]ethyl}-1-benzothiophene-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.75 517 yl)amino]ethyl}-4-(trifluoromethoxy)benzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.34 484 yl)amino]ethyl}-5-chloro-2-hydroxynicotinamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.47 529 yl)amino]ethyl}-4-(trifluoroacetyl)benzamideN-[2-({2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-2.49 524 4-yl)amino]ethyl}amino)-2-oxoethyl]-4-chlorobenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.66 517 yl)amino]ethyl}-4-phenyl-1,2,3-thiadiazole-5-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.31 441 yl)amino]ethyl}-1,2,3-thiadiazole-4-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.54 515yl)amino]ethyl}-5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.37 520yl)amino]ethyl}-1-(2-furylmethyl)-5-oxopyrrolidine-3-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.60 493 yl)amino]ethyl}-3-tert-butyl-1-methyl-1H-pyrazole-5-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.14 440 yl)amino]ethyl}-5-oxopyrrolidine-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.48 507 yl)amino]ethyl}-2-(2,5-dimethoxyphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.46 477 yl)amino]ethyl}-2-(3-methoxyphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.45 477 yl)amino]ethyl}-2-(4-methoxyphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.50 477 yl)amino]ethyl}-2-(2-methoxyphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.70 487 yl)amino]ethyl}-1,2,3,4-tetrahydronaphthalene-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.36 422 yl)amino]ethyl}-1H-pyrrole-2-carboxamide(2S)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.16 440phenylpyrimidin-4-yl)amino]ethyl}-5-oxopyrrolidine-2-carboxamide(3S,4R,5S)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.06 485phenylpyrimidin-4-yl)amino]ethyl}-3,4,5-trihydroxycyclohex-1-ene-1-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.62 453 yl)amino]ethyl}-2-cyclohexylacetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.70 498 yl)amino]ethyl}-4-(1H-pyrrol-1-yl)benzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.50 530yl)amino]ethyl}-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.77 523 yl)amino]ethyl}-2-[1,1′-biphenyl]-4-ylacetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.47 531 yl)amino]ethyl}-2-(6-methoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.49 492 yl)amino]ethyl}-2-(2-nitrophenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.55 461 yl)amino]ethyl}-2-(2-methylphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.55 461 yl)amino]ethyl}-2-(4-methylphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.57 447 yl)amino]ethyl}-3-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.58 447 yl)amino]ethyl}-4-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.53 447 yl)amino]ethyl}-2-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.54 461 yl)amino]ethyl}-2-(3-methylphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.52 477 yl)amino]ethyl}-2-phenoxypropanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.47 477 yl)amino]ethyl}-1,3-benzodioxole-5-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.45 447 yl)amino]ethyl}-2-phenylacetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.52 449 yl)amino]ethyl}bicyclo[2.2.1]hept-5-ene-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.35 463 yl)amino]ethyl}-2-hydroxy-2-phenylacetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.69 513 yl)amino]ethyl}-2-(2-naphthyloxy)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.75 501 yl)amino]ethyl}-1-phenylcyclopentanecarboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.50 463 yl)amino]ethyl}-2-sulfanylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.30 427 yl)amino]ethyl}tetrahydrofuran-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.87 515 yl)amino]ethyl}-2-cyclopentyl-2-phenylacetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.86 489 yl)amino]ethyl}-4-tert-butylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.79 491 yl)amino]ethyl}adamantane-1-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.48 463 yl)amino]ethyl}-4-methoxybenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-3.07 515 yl)amino]ethyl}-4-cyclohexylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.63 483 yl)amino]ethyl}-1-naphthamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.49 433 yl)amino]ethyl}benzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.77 525 yl)amino]ethyl}-4-bromo-3-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.73 482 yl)amino]ethyl}-5-chloro-2-hydroxybenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.56 476 yl)amino]ethyl}-4-(dimethylamino)benzamide2-(acetylamino)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.12428 phenylpyrimidin-4-yl)amino]ethyl}acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.32 493 yl)amino]ethyl}-2-(4-hydroxy-3-methoxyphenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.48 463 yl)amino]ethyl}-3-hydroxy-4-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.67 457 yl)amino]ethyl}-3-phenylprop-2-ynamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.73 501 yl)amino]ethyl}-4-fluoro-1-naphthamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.56 477 yl)amino]ethyl}-5-formyl-2-hydroxybenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.56 437 yl)amino]ethyl}cyclohex-1-ene-1-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.61 525 yl)amino]ethyl}-2-(4-bromophenyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.52 479 yl)amino]ethyl}-2-(methylsulfanyl)benzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.37 511 yl)amino]ethyl}-4-(methylsulfonyl)benzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.75 537 yl)amino]ethyl}-4-benzoylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.75 501 yl)amino]ethyl}-4-(trifluoromethyl)benzamide4-acetyl-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.46 475phenylpyrimidin-4-yl)amino]ethyl}benzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.51 458 yl)amino]ethyl}-4-cyanobenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.72 501 yl)amino]ethyl}-3-(trifluoromethyl)benzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.49 458 yl)amino]ethyl}-3-cyanobenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.12 473 yl)amino]ethyl}-1H-benzimidazole-5-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.79 523 yl)amino]ethyl}-2,2-diphenylacetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.70 461 yl)amino]ethyl}-4-ethylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.60 449 yl)amino]ethyl}-2-hydroxybenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.67 513 yl)amino]ethyl}-3-bromobenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.28 427 yl)amino]ethyl}-4-oxopentanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.67 513 yl)amino]ethyl}-2-[(4-chlorophenyl)sulfanyl]acetamide4-acetyl-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.39 492phenylpyrimidin-4-yl)amino]ethyl}-3,5-dimethyl-1H-pyrrole-2- carboxamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.58 465phenylpyrimidin-4-yl)amino]ethyl}-3-thien-3-ylprop-2-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.59 596 yl)amino]ethyl}-2-(2-furyl)-2-(4-phenylpiperazin-1-yl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.23 522 yl)amino]ethyl}-2-(2-furyl)-2-morpholin-4-ylacetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.13 487 yl)amino]ethyl}-2-methyl-1H-benzimidazole-5-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.35 399 yl)amino]ethyl}-2-methylpropanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.33 519 yl)amino]ethyl}-2-(1H-benzimidazol-2-ylsulfanyl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.36 500 yl)amino]ethyl}-2-hydroxyquinoline-4-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.63 473 yl)amino]ethyl}-5-chlorothiophene-2-carboxamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.61 484phenylpyrimidin-4-yl)amino]ethyl}-3-(3-cyanophenyl)prop-2-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.54 484 yl)amino]ethyl}-5-nitrothiophene-3-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.41 517 yl)amino]ethyl}-5-(methylsulfonyl)thiophene-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.69 507 yl)amino]ethyl}-4-(trifluoromethyl)cyclohexanecarboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.54 483 yl)amino]ethyl}-3-ethoxythiophene-2-carboxamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.51 449phenylpyrimidin-4-yl)amino]ethyl}-3-(2-furyl)prop-2-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.81 519 yl)amino]ethyl}-2,3,5,6-tetrafluoro-4-methylbenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.46 483 yl)amino]ethyl}-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.77 513phenylpyrimidin-4-yl)amino]ethyl}-3-(2,3,4-trifluorophenyl)prop-2-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.58 500 yl)amino]ethyl}-8-hydroxyquinoline-2-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.52 499 yl)amino]ethyl}-6-hydroxy-2-naphthamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.93 501phenylpyrimidin-4-yl)amino]ethyl}-3-(4-isopropylphenyl)prop-2- enamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.59 465phenylpyrimidin-4-yl)amino]ethyl}-3-thien-2-ylprop-2-enamide(3E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.64 473phenylpyrimidin-4-yl)amino]ethyl}-4-phenylbut-3-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.47 544 yl)amino]ethyl}-1-benzoylpiperidine-4-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.34 468 yl)amino]ethyl}-4-nitro-1H-pyrazole-3-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.23 484yl)amino]ethyl}-2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.66 517 yl)amino]ethyl}-5-(1,2-dithiolan-3-yl)pentanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.44 471yl)amino]ethyl}-2-methyl-5,6-dihydro-1,4-oxathiine-3-carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.47 451 yl)amino]ethyl}-3-(2-furyl)propanamide(2E,4E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.75 485phenylpyrimidin-4-yl)amino]ethyl}-5-phenylpenta-2,4-dienamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.29 430 yl)amino]ethyl}-3-nitropropanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.58 467 yl)amino]ethyl}-2-oxo-2-thien-2-ylacetamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.30 460phenylpyrimidin-4-yl)amino]ethyl}-3-pyridin-2-ylprop-2-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.61 492 yl)amino]ethyl}-3-methyl-2-nitrobenzamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.54 467 yl)amino]ethyl}-3-thien-2-ylpropanamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.21 495yl)amino]ethyl}-2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.60 525 yl)amino]ethyl}-4′-hydroxy[1,1′-biphenyl]-4-carboxamide(4R)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.24 458phenylpyrimidin-4-yl)amino]ethyl}-2-oxo-1,3-thiazolidine-4- carboxamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.53 437 yl)amino]ethyl}cyclohex-3-ene-1-carboxamide ethyl(2E)-4-({2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.46 455phenylpyrimidin-4-yl)amino]ethyl}amino)-4-oxobut-2-enoateN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.40 477 yl)amino]ethyl}-3-(4-hydroxyphenyl)propanamide(2E)-N-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2- 2.63 459phenylpyrimidin-4-yl)amino]ethyl}-3-phenylprop-2-enamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.20 371 yl)amino]ethyl}acetamideN-{2-[(6-{[2-(acetylamino)ethyl]amino}-5-methyl-2-phenylpyrimidin-4-2.28 385 yl)amino]ethyl}propanamide

EXAMPLE 11

Synthesis of Compounds 46.1-46.82

2-(4-Chlorophenyl)-5-methylpyrimidine-4,6-diol (42)

To ethanol (20 ml) was added sodium ethoxide solution (7.76 ml of a 21%wt solution in ethanol), 4-chlorobenzamidine hydrochloride (1.0 g) anddiethylmethylmalonate (0.89 ml). The suspension was stirred at 40° C. inan inert atmosphere for 44 hrs after which time it was cooled to 5° C.and treated dropwise with concentrated hydrochloric acid to a pH of 2.The resulting suspension was filtered and washed with excess water, thenethanol (20 ml) and diethyl ether (20 ml) affording the title compoundas a solid (1.71 g).

δ_(H) (d⁶-DMSO): 1.80 (3H, s), 7.56-7.6 (2H, d), 8.05-8.10 (2H, d); m/z(ES⁺) 237 (MH)⁺

4,6-Dichloro-2-(4-chlorophenyl)-5-methylpyrimidine (43)

2-(4-Chlorophenyl)-5-methylpyrimidine-4,6-diol was added to a mixture ofphosphorous oxychloride (4 ml) and N,N-dimethylformamide (5 drops) andthe mixture heated to reflux for 6 hrs. After this time the solvent wasremoved in vacuo. Iced water was cautiously added with stirring toreveal the title compound as a beige solid (1.83 g) after filtration anddrying in vacuo.

δ_(H) (CDCl₃): 2.43 (3H, s), 7.58-7.62 (2H, d), 8.23-8.28 (2H, m)

N-{2-[(6-Chloro-5-methyl-2-(4-chlorophenylpyrimidin-4-yl)amino]ethyl}acetamide(44)

4,6-Dichloro-2-(4-chlorophenyl)-5-methylpyrimidine (1.0 g),N-acetyethylenediamine (0.39 g) and triethylamine (0.52 ml) were addedto ethanol (100 ml) with stirring. The resulting solution was heated toreflux for 40 hrs then cooled to ambient temperature. The mother liquorwas evaporated onto silica gel and purified by column chromatography onsilica gel eluting with ethyl acetate furnishing the title compound(0.783 g). δ_(H) (CDCl₃): 1.94 (3H, s), 2.19 (3H, s), 3.55-3.62 (2H, m),3.68-3.75 (2H, m), 5.95-6.00 (1H, br s), 6.03-6.12 (1H, br s), 7.37-7.42(2H, d), 8.28-8.32 (2H, d); m/z (ES⁺) 339 (MH)⁺

N-{2-[6-(2-Aminoethylamino)-2-(4-chlorophenyl)-5-methylpyrimidin-4-ylamino]-ethyl}acetamide(45)

N-{2-[(6-Chloro-5-methyl-2-(4-chlorophenylpyrimidin-4-yl)amino]ethyl}acetamide(0.78 g) was dissolved in ethylenediamine (20 ml) and heated withstirring to reflux for 18 hrs. After cooling to ambient temperature thesolution was evaporated onto silica gel. Purification via flashchromatography on silica gel eluting with a mixture of ethyl acetate andmethanol (30:70 v/v) then methanol, then a mixture of methanol andammonium hydroxide (95:5 v/v) furnished the title compound (0.44 g).

δ_(H) (d⁶-DMSO, trace of water): 1.78 (3H, s), 1.81 (3H, s), 2.50-2.53(1H, t), 2.70-2.75 (2H, t), 2.97-3.02 (1H, q), 3.23-3.29 (2H, m, underwater peak), 3.40-3.50 (2H, m), 6.05-6.10 (1H, m), 6.15-6.20 (1H, m),7.40-7.43 (2H, d), 7.70-7.78 (1H, m), 7.88-7.95 (1H, m), 8.27-8.32 (2H,d); m/z (ES⁺) 363 (MH)⁺

Library Example:

N-(2-{[6-{[2-(Acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5-methylpyrimidin-4-yl]amino}ethyl)isoquinoline-3-carboxamide(46.1)

A solution of 3-isoquinoline carboxylic acid (60 μl of a 0.3M solutionin NMP), HATU (60 μl of a 0.3M solution in NMP) anddiisopropylethylamine (60 μl of a 0.3M solution in NMP) was shaken atambient temperature in a well of a 96 position microtitre plate for 20min.N-{2-[6-(2-Aminoethylamino)-2-(4-chlorophenyl)-5-methylpyrimidin-4-ylamino]-ethyl}acetamide(30 μl of a 0.3M solution in NMP) was then added and the mixture shakenfor a further 12 hrs. Purification via ion exchange silica (SCX) yieldsthe title compound.

LCMS (Method A) RT=2.98 min; m/z (ES⁺) 518 (MH)⁺

The following compounds 46.2-46.82 were synthesised in an analogousmanner: Mass Ion Retention (ES⁺) Name Time (min) (MH)⁺N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.75 506methylpyrimidin-4-yl]amino}ethyl)-1H-indole-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.57 506methylpyrimidin-4-yl]amino}ethyl)-1H-indole-3-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.42 527methylpyrimidin-4-yl]amino}ethyl)-2-(3-hydroxy-4-methoxyphenyl)acetamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.68532 methylpyrimidin-4-yl]amino}ethyl)-3-(1H-indol-3-yl)prop-2-enamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.77538 methylpyrimidin-4-yl]amino}ethyl)-3-(3-nitrophenyl)prop-2-enamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.86 497methylpyrimidin-4-yl]amino}ethyl)-2-hydroxy-4-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.96 497methylpyrimidin-4-yl]amino}ethyl)-2-hydroxy-3-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.54 468methylpyrimidin-4-yl]amino}ethyl)-3-(1H-indol-3-yl)propanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.59 525methylpyrimidin-4-yl]amino}ethyl)-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.58 514methylpyrimidin-4-yl]amino}ethyl)-2-(methylsulfanyl)nicotinamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.75 527methylpyrimidin-4-yl]amino}ethyl)-1-tert-butyl-3-methyl-1H-pyrazole-5-carboxamide N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5-2.97 551 methylpyrimidin-4-yl]amino}ethyl)-4-(trifluoromethoxy)benzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.59 541methylpyrimidin-4-yl]amino}ethyl)-2-(2,5-dimethoxyphenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.67 511methylpyrimidin-4-yl]amino}ethyl)-2-(3-methoxyphenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.59 511methylpyrimidin-4-yl]amino}ethyl)-2-(4-methoxyphenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.87 521methylpyrimidin-4-yl]amino}ethyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5-2.49 456 methylpyrimidin-4-yl]amino}ethyl)-1H-pyrrole-2-carboxamide(3S,4R,5S)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5-2.19 519methylpyrimidin-4-yl]amino}ethyl)-3,4,5-trihydroxycyclohex-1-ene-1-carboxamide N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5-2.69 495 methylpyrimidin-4-yl]amino}ethyl)-2-(2-methylphenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.71 481methylpyrimidin-4-yl]amino}ethyl)-2-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.70 497methylpyrimidin-4-yl]amino}ethyl)-2-sulfanylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 3.04 549methylpyrimidin-4-yl]amino}ethyl)-2-cyclopentyl-2-phenylacetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 3.15 571methylpyrimidin-4-yl]amino}ethyl)-4-benzoylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.99 507methylpyrimidin-4-yl]amino}ethyl)-5-chlorothiophene-2-carboxamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.85483 methylpyrimidin-4-yl]amino}ethyl)-3-(2-furyl)prop-2-enamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 3.16547 methylpyrimidin-4-yl]amino}ethyl)-3-(2,3,4-trifluorophenyl)prop-2-enamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.99499 methylpyrimidin-4-yl]amino}ethyl)-3-thien-2-ylprop-2-enamide(2E,4E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5-3.15 519 methylpyrimidin-4-yl]amino}ethyl)-5-phenylpenta-2,4-dienamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.64 419methylpyrimidin-4-yl]amino}ethyl)propanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 3.05 518methylpyrimidin-4-yl]amino}ethyl)quinoline-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.79 520methylpyrimidin-4-yl]amino}ethyl)-2-(1H-indol-3-yl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 3.01 548methylpyrimidin-4-yl]amino}ethyl)-4-(1H-indol-3-yl)butanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 3.23 548methylpyrimidin-4-yl]amino}ethyl)-5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 3.13 523methylpyrimidin-4-yl]amino}ethyl)-1-benzothiophene-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.60 563methylpyrimidin-4-yl]amino}ethyl)-4-(trifluoroacetyl)benzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.83 527methylpyrimidin-4-yl]amino}ethyl)-3-tert-butyl-1-methyl-1H-pyrazole-5-carboxamide N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5-2.69 511 methylpyrimidin-4-yl]amino}ethyl)-2-(2-methoxyphenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.81 487methylpyrimidin-4-yl]amino}ethyl)-2-cyclohexylacetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.87 532methylpyrimidin-4-yl]amino}ethyl)-4-(1H-pyrrol-1-yl)benzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.76 481methylpyrimidin-4-yl]amino}ethyl)-3-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.72 481methylpyrimidin-4-yl]amino}ethyl)-4-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.61 511methylpyrimidin-4-yl]amino}ethyl)-1,3-benzodioxole-5-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.60 481methylpyrimidin-4-yl]amino}ethyl)-2-phenylacetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.64 483methylpyrimidin-4-yl]amino}ethyl)bicyclo[2.2.1]hept-5-ene-2- carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.97 535methylpyrimidin-4-yl]amino}ethyl)-1-phenylcyclopentanecarboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 3.02 523methylpyrimidin-4-yl]amino}ethyl)-4-tert-butylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.95 525methylpyrimidin-4-yl]amino}ethyl)adamantane-1-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.66 497methylpyrimidin-4-yl]amino}ethyl)-4-methoxybenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 3.24 549methylpyrimidin-4-yl]amino}ethyl)-4-cyclohexylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.65 467methylpyrimidin-4-yl]amino}ethyl)benzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.87 495methylpyrimidin-4-yl]amino}ethyl)-4-ethylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.57 578methylpyrimidin-4-yl]amino}ethyl)-8-hydroxyquinoline-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.51 511methylpyrimidin-4-yl]amino}ethyl)-3-(4-hydroxyphenyl)propanamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.79493 methylpyrimidin-4-yl]amino}ethyl)-3-phenylprop-2-enamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.32 405methylpyrimidin-4-yl]amino}ethyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.85 517methylpyrimidin-4-yl]amino}ethyl)-1-naphthamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.94 561methylpyrimidin-4-yl]amino}ethyl)-4-bromo-3-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.69 510methylpyrimidin-4-yl]amino}ethyl)-4-(dimethylamino)benzamide2-(acetylamino)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4- 2.22 462chlorophenyl)-5-methylpyrimidin-4-yl]amino}ethyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.40 527methylpyrimidin-4-yl]amino}ethyl)-2-(4-hydroxy-3-methoxyphenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.58 497methylpyrimidin-4-yl]amino}ethyl)-3-hydroxy-4-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.69 471methylpyrimidin-4-yl]amino}ethyl)cyclohex-1-ene-1-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.69 513methylpyrimidin-4-yl]amino}ethyl)-2-(methylsulfanyl)benzamide4-acetyl-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5-2.59 509 methylpyrimidin-4-yl]amino}ethyl)benzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.87 535methylpyrimidin-4-yl]amino}ethyl)-3-(trifluoromethyl)benzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.15 507methylpyrimidin-4-yl]amino}ethyl)-1H-benzimidazole-5-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.81 547methylpyrimidin-4-yl]amino}ethyl)-3-bromobenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.37 461methylpyrimidin-4-yl]amino}ethyl)-4-oxopentanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.19 521methylpyrimidin-4-yl]amino}ethyl)-2-methyl-1H-benzimidazole-5-carboxamide N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5-2.49 433 methylpyrimidi-4-yl]amino}ethyl)-2-methylpropanamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.72518 methylpyrimidin-4-yl]amino}ethyl)-3-(3-cyanophenyl)prop-2-enamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.83 541methylpyrimidin-4-yl]amino}ethyl)-4-(trifluoromethyl)cyclohexanecarboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.67 517methylpyrimidin-4-yl]amino}ethyl)-3-ethoxythiophene-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.61 533methylpyrimidin-4-yl]amino}ethyl)-6-hydroxy-2-naphthamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 3.10535methylpyrimidin-4-yl]amino}ethyl)-3-(4-isopropylphenyl)prop-2-enamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.84 551methylpyrimidin-4-yl]amino}ethyl)-5-(1,2-dithiolan-3-yl)pentanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.58 505methylpyrimidin-4-yl]amino}ethyl)-2-methyl-5,6-dihydro-1,4-oxathiine-3-carboxamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.39494 methylpyrimidin-4-yl]amino}ethyl)-3-pyridin-2-ylprop-2-enamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.79 526methylpyrimidin-4-yl]amino}ethyl)-3-methyl-2-nitrobenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.70 501methylpyrimidin-4-yl]amino}ethyl)-3-thien-2-ylpropanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)-5- 2.65 471methylpyrimidin-4-yl]amino}ethyl)cyclohex-3-ene-1-carboxamide

EXAMPLE 12

Synthesis of Compounds 48.1-48.141

N-(2-([6-[(2-Aminoethyl)amino]-2-(4-chlorophenyl)pyrimidin-4-yl]aminoethyl)-acetamide(47)

N-(2-{[6-Chloro-2-(4-chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamide(0.90 g) was dissolved in ethylenediamine (20 ml) and heated withstirring to reflux for 18 hrs. After cooling to ambient temperature thesolution was evaporated onto silica gel. Purification via flashchromatography on silica gel eluting with increasingly polar solventsystems from ethyl acetate to methanol furnished the title compound(0.67 g).

δ_(H) (d⁶-DMSO, trace of water): 1.78 (3H, d), 2.50-2.53 (1H, t, underd⁶-DMSO peak), 2.66-2.71 (2H, m), 2.96-3.02 (1H, q), 3.23-3.29 (2H, m,under water peak), 3.40-3.50 (2H, m, under water peak), 5.33 (1H, s),6.55-6.65 (2H, m), 7.42-7.48 (2H, d), 7.90-7.95 (1H, m), 8.23-8.29 (2H,d); m/z (ES⁺) 349 (MH)⁺

Library Example:

N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-yl]amino}ethyl)quinoline-2-carboxamide(48.1)

A solution of quinaldic acid (60 μl of a 0.3M solution in NMP), HATU (60μl of a 0.3M solution in NMP) and diisopropylethylamine (60 μl of a 0.3Msolution in NMP) was shaken at ambient temperature in a well of a 96position microtitre plate for 5 min.N-(2-{[6-[(2-aminoethyl)amino]-2-(4-chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamide (30 μl of a 0.3M solution in NMP) was then added and themixture shaken for a further 48 hrs. Purification via ion exchangesilica (SCX) yields the title compound.

LCMS (Method A) RT=2.58 min; m/z (ES⁺) 504 (MH)⁺

The following compounds 48.2-48.141 were synthesised in an analogousmanner: Mass Ion Retention (ES⁺) Name Time (min) (MH)⁺N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.53 504 yl]amino}ethyl)isoquinoline-3-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.46 505 yl]amino}ethyl)quinoxaline-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.49 504 yl]amino}ethyl)isoquinoline-1-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.63 514 yl]amino}ethyl)-2-hydroxy-5-nitrobenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.37 455 yl]amino}ethyl)pyrazine-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.29 454 yl]amino}ethyl)nicotinamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-42.26 454 yl]amino}ethyl)isonicotinamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.31 470 yl]amino}ethyl)-2-hydroxynicotinamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.65 492 yl]amino}ethyl)-1H-indole-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.52 492 yl]amino}ethyl)-1H-indole-3-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.52 498 yl]amino}ethyl)-3-nitrobenzamideN-[2-({2-(4-chlorophenyl)-6-[(2-{[1-(2,7-dimethylpyrazolo[1,5- 2.40 522a]pyrimidin-6-yl)vinyl]amino}ethyl)amino]pyrimidin-4-yl}amino)ethyl]acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.40 513 yl]amino}ethyl)-2-(3-hydroxy-4-methoxyphenyl)acetamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-2.66 518 4-yl]amino}ethyl)-3-(1H-indol-3-yl)prop-2-enamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-2.67 524 4-yl]amino}ethyl)-3-(3-nitrophenyl)prop-2-enamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.24 521 yl]amino}ethyl)-3-(1H-benzimidazol-2-yl)propanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.70 483 yl]amino}ethyl)-2-hydroxy-4-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.53 499 yl]amino}ethyl)-2-hydroxy-3-methoxybenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.78 483 yl]amino}ethyl)-2-hydroxy-3-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.49 506 yl]amino}ethyl)-2-(1H-indol-3-yl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.59 520 yl]amino}ethyl)-3-(1H-indol-3-yl)propanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.42 454 yl]amino}ethyl)pyridine-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.58 534 yl]amino}ethyl)-4-(1H-indol-3-yl)butanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.37 469 yl]amino}ethyl)-5-methylpyrazine-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.78 534yl]amino}ethyl)-5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.50 511yl]amino}ethyl)-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.47 500 yl]amino}ethyl)-2-(methylsulfanyl)nicotinamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.58 513 yl]amino}ethyl)-1-tert-butyl-3-methyl-1H-pyrazole-5-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.71 509 yl]amino}ethyl)-1-benzothiophene-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.76 537 yl]amino}ethyl)-4-(trifluoromethoxy)benzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.45 504 yl]amino}ethyl)-5-chloro-2-hydroxynicotinamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-2.91 5774-yl]amino}ethyl)-4-oxo-4-(2,3,4,5,6-pentamethylphenyl)but-2-enamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.52 549 yl]amino}ethyl)-4-(trifluoroacetyl)benzamideN-{2-[(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.58 544 yl]amino}ethyl)amino]-2-oxoethyl}-4-chlorobenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.26 487 yl]amino}ethyl)-2,4-dihydroxypyrimidine-5-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.39 461 yl]amino}ethyl)-1,2,3-thiadiazole-4-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.60 535yl]amino}ethyl)-5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.50 540yl]amino}ethyl)-1-(2-furylmethyl)-5-oxopyrrolidine-3-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.63 513 yl]amino}ethyl)-3-tert-butyl-1-methyl-1H-pyrazole-5-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.55 512 yl]amino}ethyl)-2-(4-nitrophenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.50 497 yl]amino}ethyl)-2-(3-methoxyphenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.49 497 yl]amino}ethyl)-2-(4-methoxyphenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.52 497 yl]amino}ethyl)-2-(2-methoxyphenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.70 507 yl]amino}ethyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide(2S)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-2.50 497 4-yl]amino}ethyl)-2-hydroxy-3-phenylpropanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.76 507 yl]amino}ethyl)-3,5-dimethylisoxazole-4-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.45 442 yl]amino}ethyl)-1H-pyrrole-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.67 479 yl]amino}ethyl)-4-vinylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.68 473 yl]amino}ethyl)-2-cyclohexylacetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.74 518 yl]amino}ethyl)-4-(1H-pyrrol-1-yl)benzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.78 543 yl]amino}ethyl)-2-[1,1′-biphenyl]-4-ylacetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.53 551 yl]amino}ethyl)-2-(6-methoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.52 512 yl]amino}ethyl)-2-(3-nitrophenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.58 479 yl]amino}ethyl)-2-(2-methylphenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.58 481 yl]amino}ethyl)-2-(4-methylphenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.59 467 yl]amino}ethyl)-3-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.58 467 yl]amino}ethyl)-4-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.53 467 yl]amino}ethyl)-2-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.57 481 yl]amino}ethyl)-2-(3-methylphenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.92 509 yl]amino}ethyl)-4-butylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.61 498 yl]amino}ethyl)-4-nitrobenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.60 497 yl]amino}ethyl)-2-phenoxypropanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.52 497 yl]amino}ethyl)-1,3-benzodioxole-5-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.51 467 yl]amino}ethyl)-2-phenylacetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.57 469 yl]amino}ethyl)bicyclo[2.2.1]hept-5-ene-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.43 483 yl]amino}ethyl)-2-hydroxy-2-phenylacetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.74 533 yl]amino}ethyl)-2-(2-naphthyloxy)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.76 521 yl]amino}ethyl)-1-phenylcyclopentanecarboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.55 483 yl]amino}ethyl)-2-sulfanylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.36 447 yl]amino}ethyl)tetrahydrofuran-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.83 535 yl]amino}ethyl)-2-cyclopentyl-2-phenylacetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.83 509 yl]amino}ethyl)-4-tert-butylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.76 511 yl]amino}ethyl)adamantane-1-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.55 483 yl]amino}ethyl)-4-methoxybenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-3.04 535 yl]amino}ethyl)-4-cyclohexylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.64 503 yl]amino}ethyl)-1-naphthamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.52 453 yl]amino}ethyl)benzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.40 513 yl]amino}ethyl)-3-(2,4-dihydroxyphenyl)propanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.74 547 yl]amino}ethyl)-4-bromo-3-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.73 503 yl]amino}ethyl)-5-chloro-2-hydroxybenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.56 496 yl]amino}ethyl)-4-(dimethylamino)benzamide2-(acetylamino)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4- 2.20 448chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.37 513 yl]amino}ethyl)-2-(4-hydroxy-3-methoxyphenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.61 483 yl]amino}ethyl)-3-hydroxy-4-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.79 521 yl]amino}ethyl)-4-fluoro-1-naphthamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.73 497 yl]amino}ethyl)-5-formyl-2-hydroxybenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.68 457 yl]amino}ethyl)cyclohex-1-ene-1-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.93 529 yl]amino}ethyl)[1,1′-biphenyl]-4-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.74 547 yl]amino}ethyl)-2-(4-bromophenyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.65 499 yl]amino}ethyl)-2-(methylsulfanyl)benzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.69 478 yl]amino}ethyl)-4-cyanobenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.24 493 yl]amino}ethyl)-1H-benzimidazole-5-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.86 543 yl]amino}ethyl)-2,2-diphenylacetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.73 481 yl]amino}ethyl)-4-ethylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.77 533 yl]amino}ethyl)-3-bromobenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.74 533 yl]amino}ethyl)-2-[(4-chlorophenyl)sulfanyl]acetamide4-acetyl-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4- 2.55 512chlorophenyl)pyrimidin-4-yl]amino}ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-2.65 485 4-yl]amino}ethyl)-3-thien-3-ylprop-2-enamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.34 542 yl]amino}ethyl)-2-(2-furyl)-2-morpholin-4-ylacetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.22 507 yl]amino}ethyl)-2-methyl-1H-benzimidazole-5-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.47 419 yl]amino}ethyl)-2-methylpropanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.50 539 yl]amino}ethyl)-2-(1H-benzimidazol-2-ylsulfanyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.42 520 yl]amino}ethyl)-2-hydroxyquinoline-4-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.75 493 yl]amino}ethyl)-5-chlorothiophene-2-carboxamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-2.70 504 4-yl]amino}ethyl)-3-(3-cyanophenyl)prop-2-enamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.65 504 yl]amino}ethyl)-5-nitrothiophene-3-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.57 537 yl]amino}ethyl)-5-(methylsulfonyl)thiophene-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.77 527 yl]amino}ethyl)-4-(trifluoromethyl)cyclohexanecarboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.64 503 yl]amino}ethyl)-3-ethoxythiophene-2-carboxamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-2.63 469 4-yl]amino}ethyl)-3-(2-furyl)prop-2-enamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.82 539 yl]amino}ethyl)-2,3,5,6-tetrafluoro-4-methylbenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.57 523 yl]amino}ethyl)-5-bromo-2-furamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.56 503 yl]amino}ethyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-2.79 533 4-yl]amino}ethyl)-3-(2,3,4-trifluorophenyl)prop-2-enamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.68 520 yl]amino}ethyl)-8-hydroxyquinoline-2-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.64 519 yl]amino}ethyl)-6-hydroxy-2-naphthamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-2.97 521 4-yl]amino}ethyl)-3-(4-isopropylphenyl)prop-2-enamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-2.67 485 4-yl]amino}ethyl)-3-thien-2-ylprop-2-enamide(3E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-2.72 493 4-yl]amino}ethyl)-4-phenylbut-3-enamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.59 564 yl]amino}ethyl)-1-benzoylpiperidine-4-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.46 527 yl]amino}ethyl)-4-[(aminocarbothioyl)amino]benzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.81 537 yl]amino}ethyl)-5-(1,2-dithiolan-3-yl)pentanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.59 491yl]amino}ethyl)-2-methyl-5,6-dihydro-1,4-oxathiine-3-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.39 459 yl]amino}ethyl)-2-(1H-tetraazol-1-yl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.62 471 yl]amino}ethyl)-3-(2-furyl)propanamide(2E,4E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4- 2.88 505chlorophenyl)pyrimidin-4-yl]amino}ethyl)-5-phenylpenta-2,4-dienamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.46 450 yl]amino}ethyl)-3-nitropropanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.74 560 yl]amino}ethyl)-2-(4-methylphenoxy)nicotinamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-2.41 480 4-yl]amino}ethyl)-3-pyridin-2-ylprop-2-enamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.64 512 yl]amino}ethyl)-3-methyl-2-nitrobenzamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.64 487 yl]amino}ethyl)-3-thien-2-ylpropanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.40 515yl]amino}ethyl)-2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.70 545 yl]amino}ethyl)-4′-hydroxy[1,1′-biphenyl]-4-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.65 457 yl]amino}ethyl)cyclohex-3-ene-1-carboxamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.53 497 yl]amino}ethyl)-3-(4-hydroxyphenyl)propanamide(2E)-N-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-2.74 479 4-yl]amino}ethyl)-3-phenylprop-2-enamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.62 571 yl]amino}ethyl)-3-(3,4,5-trimethoxyphenyl)propanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.35 391 yl]amino}ethyl)acetamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.43 405 yl]amino}ethyl)propanamideN-(2-{[6-{[2-(acetylamino)ethyl]amino}-2-(4-chlorophenyl)pyrimidin-4-2.88 534 yl]amino}ethyl)-2-hydroxy-5-(1H-pyrrol-1-yl)benzamide

EXAMPLE 13

Synthesis of Compounds 49.54-49.55

2-({2-Phenyl-6-[({4-[(2E)-3-phenylprop-2-enyl]piperazin-1-yl}acetyl)amino]pyrimidin-4-yl}amino)acetamide(49.54)

To a crude sample ofN-(6-chloro-2-phenylpyrimidin-4-yl)-2-{4-[(2E)-3-phenylprop-2-enyl]piperazin-1-yl}acetamide(22.54) (0.75 g in 60 ml DMSO) were added glycinamide hydrochloride(1.85 g in 10 ml DMSO) and N,N-diisopropylethylamine (2.96 ml) and themixture heated to 100° C. for 16 hrs. The solvent was then removed invacuo and the residue purified twice by flash chromatography on silicagel using mixtures of dichloromethane and methanol (97:3, 95:5 then 93:7v/v/v). Further purification by recrystallization from methanolfurnished the title compound (32 mg over 2 steps).

δ_(H) (CDCl₃): 2.50-2.70 (8H, br s), 3.09 (2H, s), 3.17-(2H, d),4.13-4.18 (2H, d), 5.29-5.43 (2H, m), 6.04-6.12 (1H, m), 6.15-6.25 (1H,m), 6.45-6.55 (1H, m), 7.16-7.19 (3H, m), 7.22-7.26 (1H, m+CDCl₃),7.30-7.42 (2H, m), 7.37-7.42 (3H, m), 8.28-8.32 (2H, m), 9.39-9.43 (1H,br s); m/z (ES⁺) 486 (MH)⁺

N-{6-[(2-Amino-2-oxoethyl)amino]-2-phenylpyrimidin-4-yl}-2-(4-benzylpiperidin-1-yl)acetamide(49.55)

To a crude sample ofN-(6-chloro-2-phenylpyrimidin-4-yl)-2-(4-benzylpiperidin-1-yl)acetamide(22.55) (0.75 g in 60 ml DMSO) were added glycinamide hydrochloride(1.85 g in 10 ml DMSO) and N,N-diisopropylethylamine (2.96 ml) and themixture heated to 100° C. for 16 hrs. The solvent was then removed invacuo and the residue purified by flash chromatography on silica gelusing mixtures of dichloromethane and methanol (97:3, 95:5 then 93:7v/v/v). Further purification by recrystallization from methanolfurnished the title compound (326 mg over 2 steps).

δ_(H) (CDCl₃): 1.40-1.48 (2H, m), 1.58 (1H, s), 1.65-1.75 (2H, d),2.17-2.23 (2H, t), 2.58-2.61 (2H, d), 2.83-2.90 (2H, d), 3.10 (2H, s),4.20-4.22 (2H, d), 5.42-5.52 (1H, br s), 5.60-5.63 (1H, m), 6.17-6.25(1H, br s), 7.15-7.22 (3H, m), 7.27-7.37 (3H, m), 7.43-7.50 (3H, m),8.35-8.40 (2H, m), 9.57 (1H, s) m/z (ES⁺) 459 (MH)⁺

EXAMPLE 14

The biological activity of the compounds of the present invention wastested by performing a radioligand binding assay. The disclosedcompounds 8, 26, 29, 34, 36, 41, 46, 48 and 49 are A_(2b) receptorantagonists. Specifically, the compounds disclosed on pages 11-13 show agreater than tenfold selectivity for the A_(2b) adenosine receptor overthe A₁, A_(2A), and A₃ receptors and K_(i)'s <100 nM. The preparation ofthe binding assay is described below.

MATERIALS AND METHODS

Materials. [³H]-DPCPX [cyclopentyl-1,3-dipropylxanthine](120 Ci/mmol)was purchased from New England Nuclear (Boston, Mass.). The adenosinedeaminase and complete protease inhibitor cocktail tablets werepurchased from Boehringer Mannheim Corp. (Indianapolis, Ind.). Cellculture reagents were from Life Technologies (Grass Island, N.Y.) exceptfor serum that was from Hyclone (Logan, Utah).

Cell line. HEK293 stably expressing the human A_(2B) receptor were usedfor radioligand binding assays. Cells were grown in DMEM Glutamaxcontaining 10% FBS, 0.2 mg/ml G418 at 37° C. in 5% CO2/95% atmosphere.

Membrane Preparation. Cells were washed with cold PBS buffer twice,scraped off the plates, and centrifuged at 1000×g for 5 minutes. Cellswere homogenized with ice-cold buffer of 5 mM Tris, pH 7.4, 5 mM EDTA, 5mM EGTA, protease inhibitor cocktail tablets and incubated for 10 min onice. The homogenate was centrifuged at 32,000×g for 30 min.

The membranes were resuspended in buffer of 50 mM Tris, pH 7.4, 0.6 mMEDTA, 5 mM MgCl₂, stored at −80° C. until use. Protein concentration wasdetermined by the methods of Bradford.

Radioligand binding assay. Membranes were homogenized in buffercontaining 10 mM HEPES-KOH, pH 7.4 containing 1.0 mM EDTA; 2 U/mladenosine deaminase; and 0.1 mM Benzamidine and incubated for 30 min atroom temperature. Dissociation constants of radioligand (K_(d) values)and maximum binding sites (B_(max)) were determined in saturationbinding experiments. Saturation binding assays were carried out in areaction mixture containing 50 μl of membrane suspension, 25 μl of 4%DMSO, 25 μl of increasing amounts of radioligand, [³H]-DPCPX (finalconcentration 1-200 nM). Competition binding assays were performed in areaction mixture containing 50 μl of membrane suspension (˜5 μg/well),25 μl of [³H]-DPCPX (final concentration is ˜22 nM), and 25 μlcompounds. Nonspecific binding was measured in the presence of 100 μMNECA. Compounds were dissolved in DMSO and then diluted with 4% DMSO;the final maximum DMSO concentrations were 1%. Incubations were carriedout in triplicate for 1 hr at 23.5° C. Reactions were terminated byrapid filtration over GF/C filters using a cell harvester. The filterswere washed ten times with 0.4 ml of ice-cold buffer containing 10 mMHEPES-KOH, pH 7.4. The filters were dried, covered with scintillationfluid and counted with a TopCount.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, many equivalents to specificembodiments of the invention described specifically herein. Suchequivalents are intended to be encompassed in the scope of the followingclaims.

1-12. (canceled)
 13. A compound having the structure:

wherein R₁₀ is substituted or unsubstituted alkyl, —C(O)-alkyl,—C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, or a substituted orunsubstituted, monocyclic or bicyclic aryl, heterocyclic or heteroarylmoiety containing from 1 to 6 heteroatoms; and R₁₁ is a hydrogen orhalogen atom.
 14. The compound of claim 13, wherein R₁₀ is a substitutedor unsubstituted alkyl, —C(O)-alkyl, —C(O)-O-alkyl, cycloalkyl, alkenyl,or a substituted or unsubstituted, monocyclic or bicyclic aryl,heterocyclic or heteroaryl moiety containing from 1 to 6 heteroatoms.15. The compound of claim 14, wherein R₁₁ is hydrogen.
 16. The compoundof claim 14, wherein R₁₁ is a halogen atom.
 17. The compound of claim13, wherein any heterocyclic or heteroaryl ring, if present, is apiperazine, piperidine, (1,4)diazepan, pyrazine, pyridine, pyrrolidine,pyrazole, pyrimidine, thiophene, imidazole, azetidine, pyrrole,benzothiazole, benzodioxolane, dithiolane, oxathiine, imidazolidine,quinoline, isoquinoline, dihydroisoquinoline, indole, isoindole,triazaspiro[4.5]decane, morpholine, furan or an isothiazole ring.
 18. Acompound having the structure:

wherein, R₁₀ is substituted or unsubstituted alkyl, —C(O)-alkyl,—C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, or a substituted orunsubstituted monocyclic or bicyclic aryl, heterocyclic or heteroarylmoiety containing from 1 to 6 heteroatoms; R₁₁ is a hydrogen or halogenatom; and R₁₂ is hydrogen, alkyl, halogen or cyano.
 19. The compound ofclaim 18, wherein, R₁₀ is substituted or unsubstituted alkyl,—C(O)-alkyl, —C(O)-O-alkyl, cycloalkyl, alkenyl, or a substituted orunsubstituted monocyclic or bicyclic aryl, heterocyclic or heteroarylmoiety containing from 1 to 6 heteroatoms; and R₁₂ is hydrogen ormethyl.
 20. The compound of claim 19, wherein R₁₁ is hydrogen.
 21. Thecompound of claim 20, wherein R₁₂ is hydrogen.
 22. The compound of claim20, wherein R₁₂ is methyl.
 23. The compound of claim 19, wherein R₁₁ isa halogen atom.
 24. The compound of claim 23, wherein R₁₂ is hydrogen.25. The compound of claim 23, wherein R₁₂ is methyl.
 26. The compound ofclaim 18, wherein any heterocyclic or heteroaryl ring, if present, is apiperazine, piperidine, (1,4)diazepan, pyrazine, pyridine, pyrrolidine,pyrazole, pyrimidine, thiophene, imidazole, azetidine, pyrrole,benzothiazole, benzodioxolane, dithiolane, oxathiine, imidazolidine,quinoline, isoquinoline, dihydroisoquinoline, indole, isoindole,triazaspiro[4.5]decane, morpholine, furan or an isothiazole ring.
 27. Acompound having the structure:

wherein R_(a) is Cl, Br or I; and R₁₂ is hydrogen, alkyl, halogen orcyano.
 28. The compound of claim 27, wherein R_(a) is Cl.
 29. Thecompound of claim 27, wherein R_(a) is Br.
 30. A compound having thestructure:

wherein R_(b) is hydrogen or methyl.
 31. The compound of claim 30,wherein R_(b) is hydrogen.
 32. The compound of claim 30, wherein R_(b)is methyl.
 33. A compound having the structure:

wherein, R_(c) is a halogen atom; R₁₁ is a hydrogen or halogen atom; andR₁₂ is hydrogen, alkyl, halogen or cyano.
 34. The compound of claim 33,wherein R_(c) is Cl.
 35. The compound of claim 34, wherein R₁₁ ishydrogen.
 36. The compound of claim 35, wherein R₁₂ is hydrogen.
 37. Thecompound of claim 35, wherein R₁₂ is methyl.
 38. The compound of claim34, wherein R₁₁ is Cl.
 39. The compound of claim 38, wherein R₁₂ ishydrogen.
 40. The compound of claim 38, wherein R₁₂ is methyl. 41-57.(canceled)
 58. A compound having the structure:

wherein, R₁₃ is a substituted or unsubstituted (C₁-C₄)alkyl, branchedalkyl or (C₃-C₇)cycloalkyl, wherein the substituent is —OH, OR, —NH₂,—NR₁₈R₁₉, —R₂₀NOCR₂₁, R₂₂R₂₃NCO—, carboxyl, carbamoyl (—R₂₀NOCNR₂₂R₂₃),carbamate (—R₂₀NOCOR), or a heterocyclic ring; or a substituted orunsubstituted aryl or heterocyclic ring wherein any substituent, ifpresent, is OH, OR, halogen, NH₂, or NHR; -wherein R is alkyl,cycloalkyl, aryl, heteroaryl, susbtituted alkyl, aryl, arylalkyl, orheterocyclic; R₁₄ is substituted or unsubstituted phenyl, wherein thesubstituent, if present, is halogen, OH, NH₂, OR, NHR or a 5-6 memberedheterocyclic ring; R₁₅ is H, or alkyl; R₁₆ is H, substituted orunsubstituted alkyl or aryl, or R₁₅ and R₁₆ are joined to form aheterocyclic ring; X is CHR₁₇, CR₂₄R₂₅, O or NR; R₁₇ is H, substitutedor unsubstituted alkyl, aryl, arylalkyl, heterocyclic, heterocyclicalkyl, OH, OR, NH₂, NR₁₈R₁₉, R₂₀NOCR₂₁, R₂₂R₂₃NCO—, carboxyl, carbamoyl(—R₂₀NOCNR₂₂R₂₃), carbamate (—R₂₀NOCOR), or (C₃-C₇)cycloalkyl; R₁₈ andR₁₉ are each independently hydrogen, substituted or unsubstituted alkylor aryl or R₁₈NR₁₉ together form a heterocyclic ring of between 4 and 8members; R₂₀ and R₂₁ are each independently a substituted orunsubstituted alkyl, aryl, or alkylaryl moiety; R₂₂ and R₂₃ are eachindependently hydrogen, substituted or unsubstituted alkyl, aryl oralkylaryl, or R₂₂NR₂₃ together form a heterocyclic ring of between 4 and8 members; R₂₄ and R₂₅ are each independently hydrogen, substituted orunsubstituted alkyl, cycloalkyl, aryl, heterocyclic or R₂₄ and R₂₅together form a 3-7 membered ring system or a dioxalane or dioxane ringsystem; and p is 0, 1 or
 2. 59-66. (canceled)
 67. A pharmaceuticalcomposition comprising the compound of claim 13 and a pharmaceuticallyacceptable carrier.
 68. The pharmaceutical composition of claim 67,formulated for oral, topical, parenteral or nasal administration.
 69. Amethod for treating asthma, urticaria, scleroderm arthritis, myocardialinfarction, myocardial reperfusion after ischemia, diabetic retinopathy,retinopathy of prematurity, diabetes, diarrhea, inflammatory boweldisease, proliferating tumor or is associated with mast celldegranulation, vasodilation, hypertension, hypersensitivity or therelease of allergic mediators by administering an effective amount ofthe compound according to claim
 13. 70. A pharmaceutical compositioncomprising the compound of claim 18 and a pharmaceutically acceptablecarrier.
 71. The pharmaceutical composition of claim 70, formulated fororal, topical, parenteral or nasal administration.
 72. A method fortreating asthma, urticaria, scleroderm arthritis, myocardial infarction,myocardial reperfusion after ischemia, diabetic retinopathy, retinopathyof prematurity, diabetes, diarrhea, inflammatory bowel disease,proliferating tumor or is associated with mast cell degranulation,vasodilation, hypertension, hypersensitivity or the release of allergicmediators by administering an effective amount of the compound accordingto claim
 18. 73. A pharmaceutical composition comprising the compound ofclaim 27 and a pharmaceutically acceptable carrier.
 74. Thepharmaceutical composition of claim 73, formulated for oral, topical,parenteral or nasal administration.
 75. A method for treating asthma,urticaria, scleroderm arthritis, myocardial infarction, myocardialreperfusion after ischemia, diabetic retinopathy, retinopathy ofprematurity, diabetes, diarrhea, inflammatory bowel disease,proliferating tumor or is associated with mast cell degranulation,vasodilation, hypertension, hypersensitivity or the release of allergicmediators by administering an effective amount of the compound accordingto claim
 27. 76. A pharmaceutical composition comprising the compound ofclaim 30 and a pharmaceutically acceptable carrier.
 77. Thepharmaceutical composition of claim 76, formulated for oral, topical,parenteral or nasal administration.
 78. A method for treating asthma,urticaria, scleroderm arthritis, myocardial infarction, myocardialreperfusion after ischemia, diabetic retinopathy, retinopathy ofprematurity, diabetes, diarrhea, inflammatory bowel disease,proliferating tumor or is associated with mast cell degranulation,vasodilation, hypertension, hypersensitivity or the release of allergicmediators by administering an effective amount of the compound accordingto claim
 30. 79. A pharmaceutical composition comprising the compound ofclaim 33 and a pharmaceutically acceptable carrier.
 80. Thepharmaceutical composition of claim 79, formulated for oral, topical,parenteral or nasal administration.
 81. A method for treating asthma,urticaria, scleroderm arthritis, myocardial infarction, myocardialreperfusion after ischemia, diabetic retinopathy, retinopathy ofprematurity, diabetes, diarrhea, inflammatory bowel disease,proliferating tumor or is associated with mast cell degranulation,vasodilation, hypertension, hypersensitivity or the release of allergicmediators by administering an effective amount of the compound accordingto claim
 33. 82. A pharmaceutical composition comprising the compound ofclaim 58 and a pharmaceutically acceptable carrier.
 83. Thepharmaceutical composition of claim 82, formulated for oral, topical,parenteral or nasal administration.
 84. A method for treating asthma,urticaria, scleroderm arthritis, myocardial infarction, myocardialreperfusion after ischemia, diabetic retinopathy, retinopathy ofprematurity, diabetes, diarrhea, inflammatory bowel disease,proliferating tumor or is associated with mast cell degranulation,vasodilation, hypertension, hypersensitivity or the release of allergicmediators by administering an effective amount of the compound accordingto claim 58.